AMPK-activating heterocyclic compounds and methods for using the same

ABSTRACT

Disclosed are substituted pyridine compounds as well as pharmaceutical compositions and methods of use. One embodiment is a compound having the structure 
     
       
         
         
             
             
         
       
         
         
           
             wherein E, J, T, the ring system denoted by “B”, T, R 3 , R 4 , w and x are as described herein. In certain embodiments, a compound disclosed herein activates the AMPK pathway, and can be used to treat metabolism-related disorders and conditions.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.13/194,810, filed Jul. 29, 2011, which in turn claims the benefit of theearlier filing date of U.S. Provisional Patent Application Ser. No.61/368,928, filed Jul. 29, 2010, each of which is hereby incorporatedherein by reference in its entirety.

BACKGROUND

1. Field

This disclosure relates generally to compounds, pharmaceuticalcompositions and methods of use of the compounds and compositionscontaining them. This disclosure relates more particularly to certainsubstituted pyridine compounds and pharmaceutical compositions thereof,and to methods of treating and preventing metabolic disorders such astype II diabetes, atherosclerosis and cardiovascular disease usingcertain substituted pyridine compounds.

2. Technical Background

The kinase 5″-AMP-activated protein kinase (AMPK) is well established asan important sensor and regulator of cellular energy homeostasis. Beinga multi-substrate enzyme, AMPK regulates a variety of metabolicprocesses, such as glucose transport, glycolysis and lipid metabolism.It acts as a sensor of cellular energy homeostasis and is activated inresponse to certain hormones and muscle contraction as well as tointracellular metabolic stress signals such as exercise, ischemia,hypoxia and nutrient deprivation. Once activated, AMPK switches oncatabolic pathways (such as fatty acid oxidation and glycolysis) andswitches off ATP-consuming pathways (such as lipogenesis). Activation ofthe AMPK pathway improves insulin sensitivity by directly stimulatingglucose uptake in adipocytes and muscle and by increasing fatty acidoxidation in liver and muscle, resulting in reduced circulating fattyacid levels and reduced intracellular triglyceride contents. Moreover,activation of the AMPK pathway decreases glycogen concentration byreducing the activity of glycogen synthase. Activation of the AMPKpathway also plays a protective role against inflammation andatherosclerosis. It suppresses the expression of adhesion molecules invascular endothelial cells and cytokine production from macrophages,thus inhibiting the inflammatory processes that occur during the earlyphases of atherosclerosis.

What is needed are compounds, pharmaceutical compositions and methods ofusing them to treat disease states wherein AMPK activation isbeneficial, such as type II diabetes, atherosclerosis and cardiovasculardisease.

SUMMARY

Disclosed herein are compounds having structural formula (I)

and pharmaceutically acceptable salts, prodrugs and N-oxides thereof(and solvates and hydrates thereof), in which

-   -   0 or 1 of D¹, D² and D³ is N, with the others independently        being CH or C substituted by one of the w R³;    -   E is —R², —C(O)NR¹R², —NR¹R² or —NR¹C(O)R², in which R¹ and R²        together with the nitrogen to which they are bound form Hca, or        R¹ is H, —(C₁-C₄ alkyl), —C(O)—(C₁-C₄ alkyl) or —C(O)O—(C₁-C₄        alkyl), and R² is —C(O)Hca, —(C₀-C₃ alkyl)-Ar, —(C₀-C₃        alkyl)-Het, —(C₀-C₃ alkyl)-Cak or —(C₀-C₃ alkyl)-Hca;    -   each R³ is independently selected from —(C₁-C₆ alkyl), —(C₁-C₆        haloalkyl), —(C₀-C₆ alkyl)-Ar, —(C₀-C₆ alkyl)-Het, —(C₀-C₆        alkyl)-Cak, —(C₀-C₆ alkyl)-Hca, —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆        alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰,        —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN;    -   w is 0, 1, 2 or 3;    -   each R⁴ is independently selected from —(C₁-C₆ alkyl), —(C₁-C₆        haloalkyl), —(C₀-C₆ alkyl)-Ar, —(C₀-C₆ alkyl)-Het, —(C₀-C₆        alkyl)-Cak, —(C₀-C₆ alkyl)-Hca, —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆        alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰,        —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, and two R⁴ on        the same carbon optionally combine to form oxo, and two R⁴ on        different carbons optionally combine to form a —(C₀-C₄        alkylene)- bridge;    -   x is 0, 1, 2, 3 or 4;    -   J is absent, —C(O)—, —NR¹³—, —NR¹³C(O)— or —C(O)NR¹³—, in which        R¹³ is selected from —H, —(C₁-C₄ alkyl), —C(O)—(C₁-C₄ alkyl) and        —C(O)O—(C₁-C₄ alkyl);

-   the ring system denoted by “B” is absent, arylene, heteroarylene,

-    wherein each of Y¹ and Y² is N, C or CH, provided that at least one    of Y¹ and Y² is N, p is 0, 1, 2, 3 or 4, q is 1, 2, 3 or 4, and the    sum of p and q is 1, 2, 3, 4, 5 or 6, or

-   wherein Y¹ is N or C and Y² is N, C or CH, provided that at least    one of Y¹ and Y² is N, the ring system denoted by “C” is an arylene    or a heteroarylene, p is 0, 1, 2, 3 or 4, q is 1, 2, 3 or 4, and the    sum of p and q is 1, 2, 3, 4, 5 or 6;-   T is H, —(C₁-C₆ alkyl), —(C₁-C₆ alkyl)-R²³ in which R²³ is Het or Ar    and in which one or more non-adjacent carbons of the alkyl is    optionally replaced by —O— or —S—, —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆    alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰, —(C₀-C₆    alkyl)-S(O)₀₋₂R¹⁰ or

wherein

-   -   Q is —O—(C₀-C₃ alkyl)-, —S(O)₂—, -L- or (C₀-C₃ alkyl)-, in which        each carbon of the —(C₀-C₃ alkyl)- is optionally and        independently substituted with one or two R¹⁶;    -   the ring system denoted by “A” is heteroaryl, aryl, cycloalkyl        or heterocycloalkyl;    -   each R⁵ is independently selected from —(C₁-C₆ alkyl), —(C₁-C₆        haloalkyl), —(C₀-C₆ alkyl)-Ar, —(C₀-C₆ alkyl)-Het, —(C₀-C₆        alkyl)-Cak, —(C₀-C₆ alkyl)-Hca, —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆        alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰,        —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —N₃, —SF₅, —NO₂ and —CN;        and    -   y is 0, 1, 2, 3 or 4;        in which    -   each L is independently selected        -   from —NR⁹C(O)O—, —OC(O)NR⁹—, —NR⁹C(O)—NR⁹—, —NR⁹C(O)S—,            —SC(O)NR⁹—, —NR⁹C(O)—, —C(O)—NR⁹—, —NR⁹C(S)O—, —OC(S)NR⁹—,            —NR⁹C(S)—NR⁹—, —NR⁹C(S)S—, —SC(S)NR⁹—, —NR⁹C(S)—, —C(S)NR⁹—,            —SC(O)NR⁹—, —NR⁹C(S)—, —S(O)₀₋₂—, —C(O)O, —OC(O)—, —C(S)O—,            —OC(S)—, —C(O)S—, —SC(O)—, —C(S)S—, —SC(S)—, —OC (O)O—,            —SC(O)O—, —OC(O)S—, —SC(S)O—, —OC(S)S—, —NR⁹C(NR²)NR⁹—,            —NR⁹SO₂—, —SO₂NR⁹— and —NR⁹SO₂NR⁹—,    -   each R⁶, R⁷, R⁸ and R¹⁰ is independently selected from H,        —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl), —(C₀-C₆ alkyl)-Ar, —(C₀-C₆        alkyl)-Het, —(C₀-C₆ alkyl)-Cak, —(C₀-C₆ alkyl)-Hca, —(C₀-C₆        alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-NR⁹—(C₀-C₆ alkyl),        —(C₀-C₆ alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-C(O)—(C₀-C₆        alkyl) and —(C₀-C₆ alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl),    -   each R⁹ is independently selected from —H, —(C₁-C₄ alkyl),        —C(O)—(C₁-C₄ alkyl) and —C(O)O—(C₁-C₄ alkyl),    -   each Ar is an optionally substituted aryl,    -   each Het is an optionally substituted heteroaryl,    -   each Cak is an optionally substituted cycloalkyl,    -   each Hca is an optionally substituted heterocycloalkyl, and each        alkyl is optionally substituted.

Also disclosed herein are pharmaceutical compositions. Examples of suchcompositions include those having at least one pharmaceuticallyacceptable carrier, diluent or excipient; and a compound,pharmaceutically acceptable salt, prodrug or N-oxide (or solvate orhydrate) disclosed herein.

Another aspect of the present disclosure includes methods for modulatingmetabolism in subjects. Accordingly, also disclosed are methods fortreating metabolic disorders using the presently disclosed compounds andpharmaceutical compositions.

Another aspect of the present disclosure includes methods for modulatingsphingolipid metabolism, for example modulating ceramide signalling insubjects. In one aspect, modulating sphingolipid metabolism includesmodulating ceramidase activity, for example by up-regulating ceramidasefunction. Accordingly, also disclosed are methods for treatingceramide-linked diseases and disorders using the presently disclosedcompounds and pharmaceutical compositions.

DETAILED DESCRIPTION

One aspect of the disclosure provides compounds having structuralformula (I):

and pharmaceutically acceptable salts, prodrugs and N-oxides thereof(and solvates and hydrates thereof), in which

-   -   0 or 1 of D¹, D² and D³ is N, with the others independently        being CH or C substituted by one of the w R³;    -   E is —R², —C(O)NR¹R², —NR¹R² or —NR¹C(O)R², in which R¹ and R²        together with the nitrogen to which they are bound form Hca, or        R¹ is H, —(C₁-C₄ alkyl), —C(O)—(C₁-C₄ alkyl) or —C(O)O—(C₁-C₄        alkyl), and R² is —C(O)Hca, —(C₀-C₃ alkyl)-Ar, —(C₁-C₃        alkyl)-O—Ar, —(C₁-C₃ alkyl)-O-Het, —(C₀-C₃ alkyl)-Het, —(C₀-C₃        alkyl)-Cak or —(C₀-C₃ alkyl)-Hca;    -   each R³ is independently selected from —(C₁-C₆ alkyl), —(C₁-C₆        haloalkyl), —(C₀-C₆ alkyl)-Ar, —(C₀-C₆ alkyl)-Het, —(C₀-C₆        alkyl)-Cak, —(C₀-C₆ alkyl)-Hca, —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆        alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰,        —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN;    -   w is 0, 1, 2 or 3;    -   each R⁴ is independently selected from —(C₁-C₆ alkyl), —(C₁-C₆        haloalkyl), —(C₀-C₆ alkyl)-Ar, —(C₀-C₆ alkyl)-Het, —(C₀-C₆        alkyl)-Cak, —(C₀-C₆ alkyl)-Hca, —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆        alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰,        —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, and two R⁴ on        the same carbon optionally combine to form oxo, and two R⁴ on        different carbons optionally combine to form a —(C₀-C₄        alkylene)- bridge;    -   x is 0, 1, 2, 3 or 4;    -   J is absent, —C(O)—, —NR¹³—, —NR¹³C(O)— or —C(O)NR¹³—, in which        R¹³ is selected from —H, —(C₁-C₄ alkyl), —C(O)—(C₁-C₄ alkyl) and        —C(O)O—(C₁-C₄ alkyl);    -   the ring system denoted by “B” is absent, arylene,        heteroarylene.

-   -    wherein each of Y¹ and Y² is N, C or CH, provided that at least        one of Y¹ and Y² is N; p is 0, 1, 2, 3 or 4, q is 1, 2, 3 or 4,        and the sum of p and q is 1, 2, 3, 4, 5 or 6, or

-   wherein Y¹ is N or C and Y² is N, C or CH, provided that at least    one of Y¹ and Y² is N, the ring system denoted by “C” is an arylene    or a heteroarylene, p is 0, 1, 2, 3 or 4, q is 1, 2, 3 or 4, and the    sum of p and q is 1, 2, 3, 4, 5 or 6;-   T is H, —(C₁-C₆ alkyl), —(C₁-C₆ alkyl)-R²³ in which R²³ is Het or Ar    and in which one or more non-adjacent carbons of the alkyl is    optionally replaced by —O— or —S—, —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆    alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰, —(C₀-C₆    alkyl)-S(O)₀₋₂R¹⁰ or

wherein

-   -   Q is —O—(C₀-C₃ alkyl)-, —S(O)₂—, -L- or (C₀-C₃ alkyl)-, in which        each carbon of the —(C₀-C₃ alkyl)- is optionally and        independently substituted with one or two R¹⁶;    -   the ring system denoted by “A” is heteroaryl, aryl, cycloalkyl        or heterocycloalkyl;    -   each R⁵ is independently selected from —(C₁-C₆ alkyl), —(C₁-C₆        haloalkyl), —(C₀-C₆ alkyl)-Ar, —(C₀-C₆ alkyl)-Het, —(C₀-C₆        alkyl)-Cak, —(C₀-C₆ alkyl)-Hca, —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆        alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰,        —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —N₃, —SF₅, —NO₂ and —CN;        and    -   y is 0, 1, 2, 3 or 4;        in which    -   each L is independently selected        -   from —NR⁹C(O)O—, —OC(O)NR⁹—, —NR⁹C(O)—NR⁹—, —NR⁹C(O)S—,            —SC(O)NR⁹—, —NR⁹C(O)—, —C(O)—NR⁹—, —NR⁹C(S)O—, —OC(S)NR⁹—,            —NR⁹C(S)—NR⁹—, —NR⁹C(S)S—, —SC(S)NR⁹—, —NR⁹C(S)—, —C(S)NR⁹—,            —SC(O)NR⁹—, —NR⁹C(S)—, —S(O)₀₋₂—, —C(O)O, —OC(O)—, —C(S)O—,            —OC(S)—, —C(O)S—, —SC(O)—, —C(S)S—, —SC(S)—, —OC (O)O—,            —SC(O)O—, —OC(O)S—, —SC(S)O—, —OC(S)S—, —NR⁹C(NR²)NR⁹—,            —NR⁹SO₂—, —SO₂NR⁹— and —NR⁹SO₂NR⁹—,    -   each R⁶, R⁷, R⁸ and R¹⁰ is independently selected from H,        —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl), —(C₀-C₆ alkyl)-Ar, —(C₀-C₆        alkyl)-Het, —(C₀-C₆ alkyl)-Cak, —(C₀-C₆ alkyl)-Hca, —(C₀-C₆        alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-NR⁹—(C₀-C₆ alkyl),        —(C₀-C₆ alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-C(O)—(C₀-C₆        alkyl) and —(C₀-C₆ alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl),    -   each R⁹ is independently selected from —H, —(C₁-C₄ alkyl),        —C(O)—(C₁-C₄ alkyl) and —C(O)O—(C₁-C₄ alkyl),    -   each Ar is an optionally substituted aryl,    -   each Het is an optionally substituted heteroaryl,    -   each Cak is an optionally substituted cycloalkyl,    -   each Hca is an optionally substituted heterocycloalkyl, and    -   each alkyl is optionally substituted.

In certain embodiments of the presently disclosed compounds ofstructural formula (I) as described above, the compound has structuralformula (II):

and pharmaceutically acceptable salts, prodrugs and N-oxides thereof(and solvates and hydrates thereof), in which

-   -   E is —R², —C(O)NR¹R², —NR¹R², —NR¹C(O)R², in which R¹ and R²        together with the nitrogen to which they are bound form Hca, or        R¹ is H, —(C₁-C₄ alkyl), —C(O)—(C₁-C₄ alkyl) or —C(O)O—(C₁-C₄        alkyl), and R² is —C(O)Hca, —(C₀-C₃ alkyl)-Ar, —(C₀-C₃        alkyl)-Het, —(C₀-C₃ alkyl)-Cak or —(C₀-C₃ alkyl)-Hca;    -   each R³ is independently selected from —(C₁-C₆ alkyl), —(C₁-C₆        haloalkyl), —(C₀-C₆ alkyl)-Ar, —(C₀-C₆ alkyl)-Het, —(C₀-C₆        alkyl)-Cak, —(C₀-C₆ alkyl)-Hca, —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆        alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰,        —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN;    -   w is 0, 1, 2 or 3;    -   each R⁴ is independently selected from —(C₁-C₆ alkyl), —(C₁-C₆        haloalkyl), —(C₀-C₆ alkyl)-Ar, —(C₀-C₆ alkyl)-Het, —(C₀-C₆        alkyl)-Cak, —(C₀-C₆ alkyl)-Hca, —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆        alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰,        —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, and two R⁴ on        the same carbon optionally combine to form oxo;    -   x is 0, 1, 2, 3 or 4;    -   J is absent, —C(O)—, —NR¹³—, —NR¹³C(O)— or —C(O)NR¹³—, in which        R¹³ is selected from —H, —(C₁-C₄ alkyl), —C(O)—(C₁-C₄ alkyl) and        —C(O)O—(C₁-C₄ alkyl);    -   the ring system denoted by “B” is absent, arylene,        heteroarylene, or

-   -    wherein each of Y¹ and Y² is N, C or CH, provided that at least        one of Y¹ and Y² is N; p is 0, 1, 2, 3 or 4, q is 1, 2, 3 or 4,        and the sum of p and q is 2, 3, 4, 5 or 6;    -   T is H, —(C₁-C₆ alkyl), —(C₁-C₆ alkyl)-R²³ in which R²³ is Het        or Ar and in which one or more non-adjacent carbons of the alkyl        is optionally replaced by —O— or —S—, —(C₀-C₆ alkyl)-L-R⁷,        —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆        alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰ or

wherein

-   -   Q is —O—(C₀-C₃ alkyl)-, —S(O)₂—, -L- or (C₀-C₃ alkyl)-, in which        each carbon of the —(C₀-C₃ alkyl)- is optionally and        independently substituted with one or two R¹⁶.    -   the ring system denoted by “A” is heteroaryl, aryl, cycloalkyl        or heterocycloalkyl;    -   each R⁵ is independently selected from —(C₁-C₆ alkyl), —(C₁-C₆        haloalkyl), —(C₀-C₆ alkyl)-Ar, —(C₀-C₆ alkyl)-Het, —(C₀-C₆        alkyl)-Cak, —(C₀-C₆ alkyl)-Hca, —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆        alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰,        —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN; and    -   y is 0, 1, 2, 3 or 4;        in which    -   each L is independently selected        -   from —NR⁹C(O)O—, —OC(O)NR⁹—, —NR⁹C(O)—NR⁹—, —NR⁹C(O)S—,            —SC(O)NR⁹—, —NR⁹C(O)—, —C(O)—NR⁹—, —NR⁹C(S)O—, —OC(S)NR⁹—,            —NR⁹C(S)—NR⁹—, —NR⁹C(S)S—, —SC(S)NR⁹—, —NR⁹C(S)—, —C(S)NR⁹—,            —SC(O)NR⁹—, —NR⁹C(S)—, —S(O)₀₋₂—, —C(O)O, —OC(O)—, —C(S)O—,            —OC(S)—, —C(O)S—, —SC(O)—, —C(S)S—, —SC(S)—, —OC (O)O—,            —SC(O)O—, —OC(O)S—, —SC(S)O—, —OC(S)S—, —NR⁹C(NR²)NR⁹—,            —NR⁹SO₂—, —SO₂NR⁹— and —NR⁹SO₂NR⁹—,    -   each R⁶, R⁷, R⁸ and R¹⁰ is independently selected from H,        —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl), —(C₀-C₆ alkyl)-Ar, —(C₀-C₆        alkyl)-Het, —(C₀-C₆ alkyl)-Cak, —(C₀-C₆ alkyl)-Hca, —(C₀-C₆        alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-NR⁹—(C₀-C₆ alkyl),        —(C₀-C₆ alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-C(O)—(C₀-C₆        alkyl) and —(C₀-C₆ alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl),    -   each R⁹ is independently selected from —H, —(C₁-C₄ alkyl),        —C(O)—(C₁-C₄ alkyl) and —C(O)O—(C₁-C₄ alkyl),    -   each Ar is an optionally substituted aryl,    -   each Het is an optionally substituted heteroaryl,    -   each Cak is an optionally substituted cycloalkyl,    -   each Hca is an optionally substituted heterocycloalkyl, and    -   each alkyl is optionally substituted.

In certain embodiments of the presently disclosed compounds ofstructural formula (I), the compound is not

-   5-(4-(4-cyanobenzyl)piperazine-1-carbonyl)-N-(1-(4-cyanobenzyl)piperidin-4-yl)picolinamide;-   N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide;-   N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-(trifluoromethyl)benzyl)piperazine-1-carbon    yl)picolinamide-   (S)-5-(4-(4-chlorophenyl)piperazine-1-carbonyl)-N-(1-(4-fluorobenzyl)pyrrolidin-3-yl)picolinamide;-   (S)-5-(4-(4-chlorophenyl)piperazine-1-carbonyl)-N-(1-(pyridin-4-ylmethyl)pyrrolidin-3-yl)picolinamide;-   (S)-5-(4-(4-chlorophenyl)piperazine-1-carbonyl)-N-(1-(4-cyanobenzyl)pyrrolidin-3-yl)picolinamide;-   N-(1-(4-chlorobenzyl)pyrrolidin-3-yl)-5-(4-(4-chlorophenyl)piperazine-1-carbonyl)picolinamide;    or-   5-(4-(4-chlorophenyl)piperazine-1-carbonyl)-N-(1-(4-(trifluoromethyl)benzyl)pyrrolidin-3-yl)picolinamide.

In one embodiment, the presently disclosed compounds are not compoundsdisclosed in Darwish et al., International Patent Application no.PCT/US10/22411, filed Jan. 28, 2010, which is hereby incorporated byreference in its entirety.

In certain embodiments of the presently disclosed compounds ofstructural formula (I) and (II) as described above, D¹, D² and D³ areindependently CH or C substituted by one of the w R³. In otherembodiments, D¹ is N and D² and D³ are independently CH or C substitutedby one of the w R³. In other embodiments, D² is N and D¹ and D³ areindependently CH or C substituted by one of the w R³. In otherembodiments, D³ is N and D¹ and D² are independently CH or C substitutedby one of the w R³.

In certain embodiments of the presently disclosed compounds ofstructural formula (I) and (II) as described above, J is —C(O)—, —NR¹³—,—NR¹³C(O)— or —C(O)NR¹³—, in which R¹³ is selected from —H, —(C₁-C₄alkyl), —C(O)—(C₁-C₄ alkyl) and —C(O)O—(C₁-C₄ alkyl). In certainembodiments of the compounds of structural formula (I) and (II) asdescribed above, R¹³ is H. In other embodiments, R¹³ is unsubstituted(C₁-C₄ alkyl). In certain embodiments of the compounds of structuralformula (I) and (II) as described above, J is —C(O)—. In otherembodiments, J is —NR¹³— (for example, —NH—). In still otherembodiments, J is —NR¹³C(O)— (for example, —NHC(O)—). In otherembodiments, J is —C(O)NR¹³— (for example, —C(O)NH—). In still otherembodiments, J is absent.

In the presently disclosed compounds of structural formula (I) and (II)as described above, the ring system denoted by “B” is absent, arylene,heteroarylene,

in which each of Y¹ and Y² is N, C or CH, provided that at least one ofY¹ and Y² is N; p is 0, 1, 2, 3 or 4, q is 1, 2, 3 or 4, and the sum ofp and q is 1, 2, 3, 4, 5 or 6,

wherein Y¹ is N or C and Y² is N, C or CH, provided that at least one ofY¹ and Y² is N, the ring system denoted by “C” is an arylene or aheteroarylene, p is 0, 1, 2, 3 or 4, q is 1, 2, 3 or 4, and the sum of pand q is 1, 2, 3, 4, 5 or 6.

For example, in certain embodiments of the presently disclosed compoundsof structural formula (I) and (II) as described above, (for example,those described below with respect to structural formula (IV)), the ringsystem denoted by “B” is arylene or heteroarylene. In certainembodiments, the ring system denoted by “B” is arylene (for example,phenylene such as 1,4-phenylene). In other embodiments, the ring systemdenoted by “B” is heteroarylene (for example, 1H-pyrazolylene,1H-1,2,3-triazolylene, pyridylene, furanylene or thienylene). In certainembodiments of the presently disclosed compounds of structural formula(I) as described above, the ring system denoted by “B” is monocyclicarylene or heteroarylene.

In certain embodiments of the presently disclosed compounds ofstructural formula (I) and (II) as described above, the ring systemdenoted by “B” is absent.

In certain embodiments of the presently disclosed compounds ofstructural formula (I) and (II) as described above, the ring systemdenoted by “B” is

wherein each of Y¹ and Y² is N, C or CH, provided that at least one ofY¹ and Y² is N; p is 0, 1, 2, 3 or 4, q is 1, 2, 3 or 4, and the sum ofp and q is 2, 3, 4, 5 or 6. For example, in certain embodiments, Y¹ is Nand Y² is C or CH. (When Y¹ or Y² is C, it is substituted by one of thex R⁴.) In other embodiments, Y¹ is C or CH and Y² is N. In otherembodiments, Y¹ is CF and Y² is N. In other embodiments, Y¹ and Y² areeach N. In certain embodiments of the presently disclosed compounds ofstructural formula (I) and (II) as described above, p is 1 and q is 2.For example, in one embodiment, the ring system denoted by “B” is apiperidine linked to the T moiety through its nitrogen atom. In anotherembodiment, the ring system denoted by “B” is a piperidine linked to theJ moiety through its piperidine nitrogen. In another embodiment, thering system denoted by “B” is a piperazine. In other embodiments of thepresently disclosed compounds of structural formula (I) and (II) asdescribed above, p is 1 and q is 1. For example, in certain embodiments,the ring system denoted by “B” is a pyrrolidine, for example, linked tothe J moiety through its pyrrolidine nitrogen. In still otherembodiments of the presently disclosed compounds of structural formula(I) and (II) as described above, p is 0 and q is 1. For example, incertain embodiments, the ring system denoted by “B” is an azetidine, forexample, linked to the J moiety through its azetidine nitrogen.

In certain embodiments of the presently disclosed compounds ofstructural formula (I) as described above, the ring system denoted by“B” is

wherein Y¹ is N or C and Y² is N, C or CH, provided that at least one ofY¹ and Y² is N, the ring system denoted by “C” is an arylene or aheteroarylene, p is 0, 1, 2, 3 or 4, q is 1, 2, 3 or 4, and the sum of pand q is 1, 2, 3, 4, 5 or 6. For example, in certain embodiments, Y¹ isN and Y² is C or CH. (When Y² is C, it can be substituted by one of thex R⁴.) In other embodiments, Y¹ is C and Y² is N. In other embodiments,Y¹ and Y² are each N. In certain embodiments of the presently disclosedcompounds of structural formula (I) and (II) as described above, p is 1and q is 2. In other embodiments of the presently disclosed compounds ofstructural formula (I) as described above, p is 1 and q is 1. Theheteroarylene can be, for example, a pyridine, a pyrazine, a pyrimidine,a triazine, a pyrrole, a pyrazole, an imidazole, or a triazole. In oneexample, the ring system denoted by “B” is

In the presently disclosed compounds of structural formula (I) and (II)as described above, x, the number of substituents on the ring systemdenoted by “B”, is 0, 1, 2, 3 or 4. In one embodiment, x is 0, 1, 2 or3. For example, in certain embodiments, x is 0. In other embodiments, xcan be 1 or 2.

In certain embodiments of the presently disclosed compounds ofstructural formula (I) and (II) as described above (for example, whenthe ring system denoted by “B” is

two R⁴ groups combine to form an oxo. The oxo can be bound, for example,at the position alpha to a nitrogen atom of the ring system. In otherembodiments, no two R⁴ groups combine to form an oxo.

In certain embodiments of the presently disclosed compounds ofstructural formula (I) and (II) as described above (for example, whenthe ring system denoted by “B” is

two R⁴ groups on different carbons combine to form a —(C₀-C₄ alkylene)-bridge. The alkylene bridge can form bicyclic system, for example, a[3.2.1] system, a [3.2.0] system, a [3.1.0] system, [2.2.2] system, a[2.2.1] system, a [2.1.1] system, a [2.2.0] system or a [2.1.0] system.For example, in one embodiment, ring system denoted by “B” issubstituted with R⁴ groups to form

In certain embodiments the —(C₀-C₄ alkylene)- bridge is unsubstituted.In other embodiments, it is substituted only with one or more halogens.

In certain embodiments of the presently disclosed compounds ofstructural formula (I) and (II) as described above (for example, whenthe ring system denoted by “B” is

two R⁴ moieties (for example, on the same carbon) are (C₁-C₄ alkyl) (forexample, methyl), as described below.

In certain embodiments of the presently disclosed compounds ofstructural formula (I) and (II) as described above, when x is 4, not allfour R⁴ groups are (C₁-C₆ alkyl).

In certain embodiments of the presently disclosed compounds ofstructural formula (I) and (II) as described above, each R⁴ isindependently selected from —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl) (forexample, difluoromethyl, trifluoromethyl and the like), —(C₀-C₆alkyl)-L-R⁷, —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, inwhich each R⁷, R⁸ and R¹⁰ is independently selected from H, —(C₁-C₆alkyl), —(C₁-C₆ haloalkyl), —(C₀-C₆ alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆alkyl)-NR⁹(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆alkyl)-C(O)—(C₀-C₆ alkyl) and —(C₀-C₆ alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), andin which no alkyl or haloalkyl is substituted with an aryl-,heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. Forexample, in one embodiment, each R⁴ is —(C₁-C₃ alkyl), —(C₁-C₃haloalkyl), —(C₀-C₃ alkyl)-L-R⁷, —(C₀-C₃ alkyl)-NR⁸R⁹, —(C₀-C₃alkyl)-OR¹⁰, —(C₀-C₃ alkyl)-C(O)R¹⁰, —(C₀-C₃ alkyl)-S(O)₀₋₂R¹⁰,-halogen, —NO₂ and —CN, in which each R⁷, R⁸ and R¹⁰ is independentlyselected from H, —(C₁-C₂ alkyl), —(C₁-C₂ haloalkyl), —(C₀-C₂alkyl)-L-(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-NR⁹(C₀-C₂ alkyl), —(C₀-C₂alkyl)-O—(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-C(O)—(C₀-C₂ alkyl) and —(C₀-C₂alkyl)-S(O)₀₋₂—(C₀-C₂ alkyl), and in which no alkyl or haloalkyl issubstituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group. In certain embodiments, each R⁴ isindependently halogen (e.g., F, Cl), unsubstituted (C₁-C₆ alkoxy) (e.g.,methoxy, ethoxy), —(C₁-C₆ haloalkoxy) (e.g., trifluoromethoxy), —SH,—S(unsubstituted C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —OH, —CN, —NO₂,—NH₂, —NH(unsubstituted C₁-C₄ alkyl), —N(unsubstituted C₁-C₄ alkyl)₂,—N₃, —SF₅, —C(O)—NH₂, C(O)NH(unsubstituted C₁-C₄ alkyl),C(O)N(unsubstituted C₁-C₄ alkyl)₂, —C(O)OH, C(O)O(unsubstituted C₁-C₆alkyl), —(NH)₀₋₁SO₂R³³, —(NH)₀₋₁COR³³, heterocycloalkyl optionallysubstituted with an (unsubstituted C₁-C₆ alkyl) and heteroaryloptionally substituted with an (unsubstituted C₁-C₆ alkyl), in whicheach R³³ is (unsubstituted C₁-C₆ alkyl), (C₁-C₆ haloalkyl(unsubstitutedC₃-C₈ cycloalkyl) or (C₃-C₈ heterocycloalkyl) optionally substitutedwith an (unsubstituted C₁-C₆ alkyl), and two R₄ optionally come togetherto form oxo. In certain embodiments, each R⁴ is independently methyl,ethyl, n-propyl, isopropyl, trifluoromethyl, pentafluoroethyl, acetyl,—NH₂, —OH, methoxy, ethoxy, trifluoromethoxy, —SO₂Me, -halogen, —NO₂ or—CN, and two R₄ optionally come together to form oxo.

In the presently disclosed compounds of structural formula (I) and (II)as described above, E is —R², —C(O)NR¹R², —NR¹R² or —NR¹C(O)R², in whichR¹ and R² together with the nitrogen to which they are bound form Hca,or R¹ is H, —(C₁-C₄ alkyl), —C(O)—(C₁-C₄ alkyl) or —C(O)O—(C₁-C₄ alkyl);and R² is —C(O)Hca, —(C₀-C₃ alkyl)-Ar, —(C₀-C₃ alkyl)-Het, —(C₀-C₃alkyl)-Cak or —(C₀-C₃ alkyl)-Hca. In certain embodiments, E is—C(O)NR¹R². In other embodiments, E is —NR¹R². In other embodiments, Eis —R². In still other embodiments, E is —NR¹C(O)R².

In certain embodiments of the compounds of structural formula (I) and(II) as described above, R¹ is H, —(C₁-C₄ alkyl), —C(O)—(C₁-C₄ alkyl) or—C(O)O—(C₁-C₄ alkyl); and R² is —C(O)Hca, —(C₀-C₃ alkyl)-Ar, —(C₀-C₃alkyl)-Het, —(C₀-C₃ alkyl)-Cak or —(C₀-C₃ alkyl)-Hca. In certain of thecompounds of structural formula (I) as described above, R¹ is H. Inother embodiments, R¹ is (C₁-C₄ alkyl), for example methyl, ethyl,n-propyl or isopropyl. In still other embodiments, R¹ is —C(O)—O—(C₁-C₄alkyl), for example —C(O)OCH₃ or —C(O)—O-t-butyl. In certainembodiments, no alkyl of R¹ is substituted with an aryl-, heteroaryl-,cycloalkyl- or heterocycloalkyl-containing group. In certainembodiments, any alkyl of R¹ is unsubstituted.

In certain of the compounds of structural formula (I) and (II) asdescribed above, R² is -Hca. In certain embodiments, R² is anoptionally-substituted monocyclic heterocycloalkyl. By way of example,such optionally substituted R² moieties include, without limitation,-(optionally-substituted azetidinyl), -(optionally-substitutedpyrrolidinyl), -(optionally-substituted piperidinyl),-(optionally-substituted piperazinyl) or -(optionally-substitutedazepanyl). For example, in one embodiment, R² can be -(optionallysubstituted piperidinyl) or -(optionally substituted pyrrolidinyl). Inone embodiment, R² is -(optionally substituted piperidinyl). In anotherembodiment, R² is -(optionally substituted pyrrolidinyl). In anotherembodiment, R² is -(optionally substituted piperazinyl).

In certain particular embodiments of the presently disclosed compoundsof structural formula (I) and (II) as described above, R² is-(optionally-substituted azetidin-3-yl), -(optionally substitutedpiperidin-4-yl), -(optionally substituted piperazin-4-yl), -(optionallysubstituted pyrrolidin-3-yl) or -(optionally-substituted azepan-4-yl).For example, in one embodiment, R² is -(optionally substitutedpiperidin-4-yl).

In another embodiment, R² is -(optionally substituted pyrrolidin-3-yl).In another embodiment, R² is -(optionally substituted piperazin-4-yl).

In certain particular embodiments, when R² is -(optionally substitutedpiperidin-4-yl), it is unsubstituted at its 2- and 3-positions.

In other embodiments, when R² is -(optionally substitutedpiperidin-4-yl), it is substituted with F at a 3-position. For example,R² can be

in which the R group is a further substituent, for example, as describedbelow. Such compounds can be provided as mixtures of diastereomers orenantiomers, or in diastereomerically and/or enantiomerically enrichedform. In certain embodiments, the compound is provided in substantiallydiastereomerically pure form, for example, as substantiallydiastereomerically pure cis compound, or diastereomerically pure transcompound. In certain embodiments, a compound is provided insubstantially enantiomerically pure form.

In certain embodiments of the presently disclosed compounds ofstructural formula (I) and (II) as described above, the azetidinyl,pyrrolidinyl, piperidinyl, piperazinyl and azepanyl R² moietiesdescribed above are substituted, for example, at their 1-positions. Incertain alternative embodiments, they can be substituted at their4-positions (e.g., when a piperidin-1-yl) or 3 positions (e.g., when apyrrolidin-5-yl). For example, in one embodiment, R² is substituted(e.g., at its 1-position) with —(C₀-C₃ alkyl)-Ar or —(C₀-C₃ alkyl)-Het,for example -(unsubstituted C₀-C₃ alkyl)-Ar or -(unsubstituted C₀-C₃alkyl)-Het. For example, in one particular embodiment, the azetidinyl,pyrrolidinyl, piperidinyl, piperazinyl or azepanyl R² moiety issubstituted (e.g., at its 1-position) with an optionally substitutedbenzyl or an optionally substituted phenyl. In another embodiment, theazetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or azepanyl R² moietyis substituted (e.g., at its 1-position) with a benzyl substituted withan electron withdrawing group; or a phenyl substituted with an electronwithdrawing group. For example, the benzyl or phenyl can be substitutedwith an electron withdrawing group selected from the group consisting ofhalo, cyano, —(C₁-C₄ fluoroalkyl), —O—(C₁-C₄ fluoroalkyl), —C(O)—(C₀-C₄alkyl), —C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄ alkyl),—S(O)₂O—(C₀-C₄ alkyl), SF₅, NO₂ and —C(O)—Hca in which the Hca includesa nitrogen atom to which the —C(O)— is bound, in which no alkyl,fluoroalkyl or heterocycloalkyl is substituted with an aryl, heteroaryl,cycloalkyl or heterocycloalkyl-containing group. In other embodiments,the azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or azepanyl R²moiety is substituted (e.g., at its 1-position) with an unsubstitutedbenzyl or an unsubstituted phenyl. In other embodiments, the azetidinyl,pyrrolidinyl, piperidinyl, piperazinyl or azepanyl R² moiety issubstituted (e.g., at its 1-position) with —CH(CH₃)Ar, CH(C(O)OCH₃)Ar or—C(CH₃)₂Ar.

In other embodiments of the compounds disclosed herein of structuralformula (I) and (II) as described above, the azetidinyl, pyrrolidinyl,piperidinyl, piperazinyl or azepanyl R² moiety is substituted (e.g., atits 1-position) with an optionally substituted pyridinylmethyl, anoptionally substituted furanylmethyl, an optionally substitutedthienylmethyl, an optionally substituted oxazolylmethyl, or anoptionally substituted imidazolylmethyl. For example, the azetidinyl,pyrrolidinyl, piperidinyl, piperazinyl or azepanyl R² moiety can besubstituted with an unsubstituted pyridinylmethyl, an unsubstitutedfuranylmethyl, an unsubstituted thienylmethyl, an unsubstitutedoxazolylmethyl, or an unsubstituted imidazolylmethyl. In otherembodiments, the azetidinyl, pyrrolidinyl, piperidinyl or azepanyl R²moiety can be substituted with an pyridinylmethyl, furanylmethyl,thienylmethyl, oxazolylmethyl or imidazolylmethyl substituted with anelectron withdrawing group as described above.

In certain embodiments of the compounds disclosed herein of structuralformula (I) and (II) as described above, the azetidinyl, pyrrolidinyl,piperidinyl, piperazinyl or azepanyl R² moiety is substituted (e.g., atits 1-position) with -L-Ar or -L-Het, in which Ar and Het can be, forexample, as described above with reference to —(C₀-C₃ alkyl)-Ar or—(C₀-C₃ alkyl)-Het. In one such embodiment, L is —C(O)—NR⁹—, such as—C(O)—NH—. In other embodiments of the presently disclosed compounds ofstructural formula (I) as described above, the azetidinyl, pyrrolidinyl,piperidinyl, piperazinyl or azepanyl R² moiety is substituted (e.g., atits 1-position) with —C(O)—O(C₀-C₆ alkyl), —C(O)—Het, —C(O)—Ar,—S(O)₂-Het, —S(O)₂—Ar or —S(O)₂—O(C₀-C₆ alkyl), in which Ar and Het canbe, for example, as described above with reference to —(C₀-C₃ alkyl)-Aror —(C₀-C₃ alkyl)-Het. In one embodiment, the azetidinyl, pyrrolidinyl,piperidinyl, piperazinyl or azepanyl R² moiety is substituted (e.g., atits 1-position) with —C(O)—Het or —C(O)—Ar; in another embodiment, it issubstituted (e.g., at its 1-position) with —S(O)₂-Het or —S(O)₂—Ar. Forexample, in certain embodiments, the azetidinyl, pyrrolidinyl,piperidinyl, piperazinyl or azepanyl R² moiety is substituted (e.g., atits 1-position) with an optionally-substituted benzoyl (for example,substituted with an electron withdrawing group as described above); orwith an optionally-substituted nicotinyl, isonicotinyl or picolinyl (forexample, optionally substituted with an electron withdrawing group asdescribed above). In other embodiments, the azetidinyl, pyrrolidinyl,piperidinyl, piperazinyl or azepanyl R² moiety is substituted (e.g., atits 1-position) with an unsubstituted benzoyl; or an unsubstitutednicotinoyl, isonicotinoyl or picolinoyl.

In other embodiments of the presently disclosed compounds of structuralformula (I) and (II) as described above, the azetidinyl, pyrrolidinyl,piperidinyl, piperazinyl or azepanyl R² moiety is substituted (e.g., atits 1-position) with —(C₀-C₃ alkyl)-Cak, for example -(unsubstitutedC₀-C₃ alkyl)-Cak (e.g, —CH₂-Cak) or —C(O)—Cak.

In one embodiment, R² is not an oxo-substituted heterocycloalkyl. Inanother embodiment, R² is not a tetramethyl-substitutedheterocycloalkyl.

In certain embodiments of the compounds of structural formula (I) and(II) as described above (for example, those in which E is —C(O)NR¹R²),R¹ and R² together with the nitrogen to which they are bound form Hca.In such embodiments, Hca can be, for example, an optionally-substitutedpiperidinyl, an optionally-substituted pyrrolidinyl, or anoptionally-substituted piperazinyl. When R¹ and R² together to form Hca,it can be defined and substituted as described above for R² wherein itis Hca.

In certain embodiments of the compounds of structural formula (I) and(II) as described above (for example, those in which E is —R², or—NR¹R²), R² is —C(O)Hca. In certain such embodiments, the Hca is linkedto the —C(O)— through a nitrogen. In other such embodiments, the Hca canbe linked to the —C(O)— through a carbon atom. The Hca can be definedand substituted, for example, as described above with respect to R² whenit is Hca.

In certain embodiments of the compounds of structural formula (I) asdescribed above (for example, those in which E is —R², —NR¹R² or—C(O)NR¹R²), R² is —(C₀-C₃ alkyl)-Ar or —(C₀-C₃ alkyl)-Het. For example,in certain embodiments, R² is Ar, in which the Ar can be, for example,monocyclic, such as optionally-substituted phenyl. In other embodiments,R² is —(C₁-C₃ alkyl)-(optionally-substituted phenyl), for exampleoptionally-substituted benzyl. In other embodiments, R² is Het, in whichthe Het can be, for example, monocyclic, such as optionally-substitutedpyridinyl or optionally-substituted 1H-pyrazolyl. In other embodimentsof the compounds of structural formula (I) as described above (forexample, those in which E is —C(O)NR¹R²), R² is —(C₀-C₃ alkyl)-Cak, inwhich the Cak can be, for example, monocyclic, such asoptionally-substituted cyclohexyl. The aryl, heteroaryl or cycloalkyl ofR² can be substituted, for example, as described above with reference toR² when it is Hca. For example, in certain embodiments, the aryl,heteroaryl or cycloalkyl of R² is substituted with —(C₀-C₃ alkyl)-Ar or—(C₀-C₃ alkyl)-Het, substituted as described above. In otherembodiments, the aryl, heteroaryl or cycloalkyl of R² is substitutedwith —O—(C₀-C₃ alkyl)-Ar or —O—(C₀-C₃ alkyl)-Het. In other embodiments,the aryl, heteroaryl or cycloalkyl of R² is substituted with anoptionally-substituted heterocycloalkyl, such as a mopholin-1-yl, a4-methylpiperazin-1-yl, or a pyrrolidin-1-yl. The ring system of the R²moiety can be substituted at any position. For example, in certainembodiments, the ring of a monocyclic R² moiety is substituted at the4-position, as counted from the attachment to the central pyridine,pyrazine, pyridazine or pyrimidine, or the nitrogen or carbonyl of the Emoiety. In other embodiments, the ring of a monocyclic R² moiety issubstituted at the 3-position, as counted from the attachment to thecentral pyridine, pyrazine, pyridazine or pyrimidine, or the nitrogen orcarbonyl of the E moiety.

In certain embodiments of the presently disclosed compounds ofstructural formula (I) and (II) as described above, the compound hasstructural formula (III)

in which E is —R², —C(O)NR¹R², —NR¹R² or —NR¹C(O)R², in which R¹ and R²together with the nitrogen to which they are bound form Hca, or R¹ is H,—(C₁-C₄ alkyl), —C(O)—(C₁-C₄ alkyl) or —C(O)O—(C₁-C₄ alkyl); and R² is—C(O)Hca, —(C₀-C₃ alkyl)-Ar, —(C₀-C₃ alkyl)-Het, —(C₀-C₃ alkyl)-Cak or—(C₀-C₃ alkyl)-Hca. All other variables are as described above withreference to structural formulae (I) and (II). In certain suchembodiments, E is R², —NR¹R² or —NR¹C(O)R². In certain embodiments ofthe compounds of structural formula (III), J is —C(O)—.

In certain embodiments of compounds of structural formulae (I) —(III) asdescribed above, (for example, those in which E is —C(O)NR¹R²), when R²is Hca (for example, pyrrolidine or piperidine), it is substituted withat least one fluorine, and further optionally substituted, for example,as described below. In certain embodiments of compounds of structuralformula (III) (for example, those in which E is —C(O)NR¹R²), when R² isHca (for example, pyrollidine or piperazine), it is substituted (forexample, at the nitrogen) with —C(O)—R²², —S(O)₂—R²², —C(O)—Cak,—CH₂-Cak, —CH(CH₃)—R²², —C(CH₃)₂—R²², —CH(C(O)—O(C₁-C₄ alkyl))Het, inwhich R²² is Ar or Het, and further optionally substituted, for example,as described below.

In certain embodiments of the compounds of structural formulae (I)—(III) as described above, (for example, those in which E is—C(O)NR¹R²), R¹ and R² together with the nitrogen to which they arebound form Hca, as described below. For example, R¹ and R² can togetherto form an optionally substituted piperazine or anoptionally-substituted pyrrolidine, as described below. In otherembodiments, R¹ and R² together with the nitrogen to which they arebound form an optionally-substituted spirocyclic heterocycloalkyl (forexample, 2,8-diazaspiro[4.5]decanyl), as described below.

In certain embodiments of the compounds of structural formulae (I)—(III) as described above, (for example, those in which E is—C(O)NR¹Hca), T is H, —C(O)—(C₁-C₆ alkyl) or (C₁-C₆ alkyl), for example,as described below. In other embodiments of the compounds of structuralformula (III) (for example, those in which E is —C(O)NR¹Hca), T is—C(CH₃)₂Ar, —CH₂-Het, -Het, —CH₂-Cak or Hca, for example, as describedbelow. In other embodiments of the compounds of structural formula (III)(for example, those in which E

is —C(O)NR¹Hca), T is in which Q is —C(O)— or —S(O)₂—, for example, asdescribed below.

In certain embodiments of the presently disclosed compounds ofstructural formula (I) and (II) as described above, the compound hasstructural formula (IV)

in which J is absent, —NR¹³—, —NR¹³C(O)— or —C(O)NR¹³—; and the ringsystem denoted by “B” is arylene, heteroarylene, or absent, and allother variables are as described with respect to structural formulae (I)—(III). For example, in certain embodiments of the compounds ofstructural formula (IV) as described above, J is absent. In otherembodiments, J is —NR¹³—, such as —NH—. In other embodiments, J is—NR¹³C(O)—, such as —NHC(O)—. In certain embodiments, the ring systemdenoted by “B” is arylene, such as phenylene); or heteroarylene, such as1H-pyrazolylene, 1H-1,2,3-triazolylene), with particular examples beingdescribed below. In other embodiments, the ring system denoted by “B” isabsent, with particular examples being described below. In certainembodiments of the compounds of structural formula (IV), (for example,those in which E is —C(O)NR¹R²), R² is Hca, such as piperidinyl, withparticular examples being described below.

In certain embodiments of the presently disclosed compounds ofstructural formula (I) and (II) as described above, the compound hasstructural formula (V)

in which the variables are as described above with reference tostructural formulae (I) —(III). In certain embodiments of the compoundsof structural formula (V), R² is Hca (for example, pyrrolidine orpiperidine), for example, described below. In other embodiments of thecompounds of structural formula (IV), R² is Cak, such as cyclohexyl, forexample, described below.

In certain embodiments of the presently disclosed compounds ofstructural formula (I) and (II) as described above, the compound hasstructural formula (VI)

in which Y is N, C, CF or CH, and all other variables are as describedabove with reference to structural formulae (I) —(III). For example, incertain embodiments, Y is N. In other embodiments, Y is CF or CH. Incertain embodiments of the compounds of structural formula (VI), p is 1and q is 2. In other embodiments (for example, when Y is C, CF or CH), qis 1 and p is 1. In certain embodiments of the compounds of structuralformula (VI), R² is Hca, such as pyrrolidine or piperidine.

In certain embodiments of the presently disclosed compounds ofstructural formula (I) and (II) as described above, the compound hasstructural formula (VII)

in which J is absent, —NR¹³—, —NR¹³C(O)— or —C(O)NR¹³—, and all othervariables are as described above with reference to structural formulae(I)(III). For example, in one embodiment, J is —NR¹³—C(O)—. In otherembodiments, J is —NR¹³—. In certain embodiments of the compounds ofstructural formula (VII), p is 1 and q is 2. In other embodiments, q is1 and p is 1. In other embodiments (for example, when Y is C, CF or CH),q is 1 and p is 0. In certain embodiments of the compounds of structuralformula (VII), R² is Hca, such as pyrrolidine or piperidine, particularexamples of which are further described below.

In certain embodiments of the presently disclosed compounds ofstructural formula (I) and (II) as described above, the compound hasstructural formula (VIII)

in which the variables are as described above with reference tostructural formulae (I) —(III). In certain embodiments of the compoundsof structural formula (VIII), p is 1 and q is 2. In other embodiments, qis 1 and p is 1. In other embodiments (for example, when Y is C, CF orCH), q is 1 and p is 0. In certain embodiments of the compounds ofstructural formula (VIII), R² is Hca.

In certain embodiments of the presently disclosed compounds ofstructural formulae (I)-(VIII) as described above, T is

In such embodiments, Q is —O—(C₀-C₃ alkyl)-, —S(O)₂—, L or —(C₀-C₃alkyl)- in which each carbon of the (C₀-C₃ alkyl) is optionally andindependently substituted with one or two R¹⁶, in which each R¹⁶ isindependently selected from —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl), —(C₀-C₆alkyl)-Ar, —(C₀-C₆ alkyl)-Het, —(C₀-C₆ alkyl)-Cak, —(C₀-C₆ alkyl)-Hca,—(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, andoptionally two of R¹⁶ on the same carbon combine to form oxo. In certainembodiments, each R¹⁶ is independently selected from —(C₁-C₆ alkyl),—(C₁-C₆ haloalkyl) (for example, difluoromethyl, trifluoromethyl and thelike), —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰,—(C₀-C₆ alkyl)-C(O)R¹⁰—(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN,and two R¹⁶ on the same carbon optionally combine to form an oxo, inwhich each R⁷, R⁸ and R¹⁰ is independently selected from H, —(C₁-C₆alkyl), —(C₁-C₆ haloalkyl), —(C₀-C₆ alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆alkyl)-NR⁹(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆alkyl)-C(O)—(C₀-C₆ alkyl), and —(C₀-C₆ alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), andin which no alkyl or haloalkyl is substituted with an aryl-,heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. Forexample, in particular compounds, each R¹⁶ is —(C₁-C₃ alkyl), —(C₁-C₃haloalkyl), —(C₀-C₃ alkyl)-L-R⁷, —(C₀-C₃ alkyl)-NR⁸R⁹, —(C₀-C₃alkyl)-OR¹⁰, —(C₀-C₃ alkyl)-C(O)R¹⁰, —(C₀-C₃ alkyl)-S(O)₀₋₂R¹⁰,-halogen, —NO₂ and —CN, and two R¹⁶ on the same carbon optionallycombine to form an oxo, in which each R⁷, R⁸ and R¹⁰ is independentlyselected from H, —(C₁-C₂ alkyl), —(C₁-C₂ haloalkyl), —(C₀-C₂alkyl)-L-(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-NR⁹(C₀-C₂ alkyl), —(C₀-C₂alkyl)-O—(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-C(O)—(C₀-C₂ alkyl) and —(C₀-C₂alkyl)-S(O)₀₋₂—(C₀-C₂ alkyl), and in which no alkyl or haloalkyl issubstituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group. In certain embodiments, each R¹⁶ isindependently methyl, ethyl, n-propyl, isopropyl, trifluoromethyl,pentafluoroethyl, acetyl, —NH₂, —OH, methoxy, ethoxy, trifluoromethoxy,—SO₂Me, -halogen, —NO₂, N₃, —SF₅, or —CN, and two R¹⁶ optionally cometogether to form oxo. In certain embodiments, Q has at most one R¹⁶ oran oxo substituted thereon. Q can be, for example, an unsubstituted—(C₀-C₃ alkyl)- (for example, a single bond, —CH₂— or —CH₂—CH₂—). Inother embodiments, Q is a (C₁-C₃ alkyl) having as its only substitutiona single oxo group. For example, in certain embodiments of the compoundsof structural formulae (I)-(VII) as described above, Q is —CH₂—;—CH₂CH₂—; —OCH₂CH₂—; O; a single bond; —S(O)₂—; —C(O)—; —CHF—; —CH(OH)—,—C(CH₃)₂—, or —CH(CH₃)—.

In certain embodiments of the compounds of structural formulae(I)-(VIII) as described above, T is

in which Q is —C(O)— or —S(O)₂—. In other embodiments, T is

in which Qis —C(CH₃)₂—, —CH₂CH₂—, —CH(CH₃)—, —CH(OH)— or —CHF—.

In certain embodiments of the compounds of structural formulae(I)-(VIII) as described above (for example, those in which T is notbound to a nitrogen), T is

in which Q is O.

In certain embodiments of the compounds of structural formulae(I)-(VIII) as described above (for example, those in which the ringsystem denoted by “B” is absent), T is

in which Q is —O—(C₁-C₃ alkyl)-, for example, —OCH₂— or —OCH₂CH₂—.

The number of substituents, y, on the ring system denoted by “A”, is 0,1, 2, 3 or 4. For example, in some embodiments of the presentlydisclosed compounds of structural formulae (I)-(VIII) as describedabove, y is 0, 1, 2 or 3, such as 1. In one embodiment, y is not zeroand at least one R⁵ is halo, cyano, —(C₁-C₄ haloalkyl), —O—(C₁-C₄haloalkyl), —(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl), —C(O)—(C₀-C₄ alkyl),—C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄ alkyl), —N₃, —SF₅, NO₂or —C(O)—Hca wherein the Hca contains a ring nitrogen atom through whichit is bound to the —C(O)—, and wherein no alkyl, haloalkyl orheterocycloalkyl is substituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group.

In certain embodiments of the presently disclosed compounds ofstructural formulae (I)-(VIII) as described above, each R⁵ isindependently selected from —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl) (forexample, difluoromethyl, trifluoromethyl and the like), —(C₀-C₆alkyl)-L-R⁷, —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —N₃, —SF₅, —NO₂ and—CN, in which each R⁷, R⁸ and R¹⁰ is independently selected from H,—(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl) (for example, difluoromethyl,trifluoromethyl and the like), —(C₀-C₆ alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆alkyl)-NR⁹(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆alkyl)-C(O)—(C₀-C₆ alkyl) and —(C₀-C₆ alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), andin which no alkyl or haloalkyl is substituted with an aryl-,heteroaryl-, cycloalkyl- or heterocycloalkyl-containing group. Forexample, in one embodiment, each R⁵ is —(C₁-C₃ alkyl), —(C₁-C₃haloalkyl), —(C₀-C₃ alkyl)-L-R⁷, —(C₀-C₃ alkyl)-NR⁸R⁹, —(C₀-C₃alkyl)-OR¹⁰, —(C₀-C₃ alkyl)-C(O)R¹⁰, —(C₀-C₃ alkyl)-S(O)₀₋₂R¹⁰,-halogen, —N₃, —SF₅, —NO₂ and —CN, in which each R⁷, R⁸ and R¹⁰ isindependently selected from H, —(C₁-C₂ alkyl), —(C₁-C₂ haloalkyl),—(C₀-C₂ alkyl)-L-(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-NR⁹(C₀-C₂ alkyl), —(C₀-C₂alkyl)-O—(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-C(O)—(C₀-C₂ alkyl) and —(C₀-C₂alkyl)-S(O)₀₋₂—(C₀-C₂ alkyl), and in which no alkyl or haloalkyl issubstituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group. In certain embodiments, each R⁵ isindependently halogen (e.g., F, Cl), unsubstituted (C₁-C₆ alkoxy) (e.g.,methoxy, ethoxy), —(C₁-C₆ haloalkoxy) (e.g., trifluoromethoxy), —SH,—S(unsubstituted C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —OH, —CN, —NO₂,—NH₂, —NH(unsubstituted C₁-C₄ alkyl), —N(unsubstituted C₁-C₄ alkyl)₂,—N₃, —SF₅, —C(O)—NH₂, C(O)NH(unsubstituted C₁-C₄ alkyl),C(O)N(unsubstituted C₁-C₄ alkyl)₂, —C(O)OH, C(O)O(unsubstituted C₁-C₆alkyl), —(NH)₀₋₁SO₂R³³, —(NH)₀₋₁COR³³, heterocycloalkyl optionallysubstituted with an (unsubstituted C₁-C₆ alkyl) and heteroaryloptionally substituted with an (unsubstituted C₁-C₆ alkyl), in whicheach R³³ is (unsubstituted C₁-C₆ alkyl), (C₁-C₆ haloalkyl(unsubstitutedC₃-C₈ cycloalkyl) or (C₃-C₈ heterocycloalkyl) optionally substitutedwith an (unsubstituted C₁-C₆ alkyl). In certain embodiments, each R⁵ isindependently methyl, ethyl, n-propyl, isopropyl, trifluoromethyl,pentafluoroethyl, acetyl, —NH₂, —OH, methoxy, ethoxy, trifluoromethoxy,—SO₂Me, -halogen, —NO₂, N₃, —SF₅, or —CN.

In one embodiment of the compounds of structural formulae (I)-(VIII) asdescribed above, y is 0. In another embodiment, y is 1. In anotherembodiment, y is 2.

In the presently disclosed compounds of structural formulae (I)-(VIII)as described above, the ring system denoted by “A” is heteroaryl, aryl,cycloalkyl or heterocycloalkyl. For example, in one embodiment, the ringsystem denoted by “A” is an aryl or a heteroaryl. The ring systemdenoted by “A” can be, for example, a monocyclic aryl or heteroaryl. Inone embodiment, when the “A” ring system is aryl, Q is a —(C₀-C₃ alkyl)-optionally substituted with oxo, and optionally substituted with one ormore R¹⁶. For example, Q can be a —(C₁-C₃ alkyl)- having its onlysubstitution a single oxo, or an unsubstituted —(C₀-C₃ alkyl)-. Incertain embodiments, the ring system denoted by “A” is an aryl or aheteroaryl and Q is —CH₂—; —CH₂CH₂—; a single bond; —S(O)₂—; —C(O)—; or—CH(CH₃)—. In other embodiments, the ring system denoted by “A” is anaryl or a heteroaryl and Q is —CF—, —CH(OH)— or —C(CH₃)₂—. In otherembodiments, the ring system denoted by “A” is an aryl or a heteroaryland Q is —O—, —OCH₂— or —OCH₂CH₂—.

For example, in certain embodiments of the presently disclosed compoundsof structural formulae (I)-(VIII) as described above, the ring systemdenoted by “A” is monocyclic aryl, such as phenyl. In one embodiment, yis 1 and R⁵ is attached to the phenyl in the para position relative toQ. In one embodiment, y is 1 and R⁵ is attached to the phenyl in themeta position relative to Q. In certain embodiments, y is 1 and R⁵ isselected from the group consisting of halo, cyano, —(C₁-C₄ haloalkyl),—O—(C₁-C₄ haloalkyl), —(C₁-C₄ alkyl), —O—(C₁-C₄ alkyl), —C(O)—(C₀-C₄alkyl), —C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄ alkyl), NO₂ and—C(O)—Hca in which the Hca contains a ring nitrogen atom through whichit is bound to the —C(O)—, and in which no (C₀-C₄ alkyl) or (C₁-C₄alkyl) is substituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group. R⁵ can be, for example, —Cl, —F,cyano, —N₃, SF₅, —C(O)CH₃, —C(O)OH, —C(O)NH₂, methoxy, trifluoromethyl,difluoromethyl, difluoromethoxy or trifluoromethoxy. In anotherembodiment, the

moiety is a 3,4-dihalophenyl, a 3,5-dihalophenyl, a3-cyano-5-methoxyphenyl, a 4-cyano-3-halophenyl, or a3-halo-4-methoxyphenyl.

In another embodiment of the presently disclosed compounds of structuralformulae (I)-(VIII) as described above, the ring system denoted by “A”is a heteroaryl. For example, in certain embodiments, the ring systemdenoted by “A” is a pyridyl, a thienyl, or a furanyl. In anotherembodiment, the ring system denoted by “A” is an isoxazolyl. In oneembodiment, when the “A” ring system is heteroaryl, Q is a —(C₀-C₃alkyl)- optionally substituted with oxo, and optionally substituted withone or more R¹⁶. For example, Q can be a —(C₁-C₃ alkyl)- having its onlysubstitution a single oxo, or an unsubstituted —(C₀-C₃ alkyl)-. Incertain embodiments, the ring system denoted by “A” is an aryl or aheteroaryl and Q is —CH₂—; a single bond; —S(O)₂—; —C(O)—; or —CH(CH₃)—.In other embodiments, the ring system denoted by “A” is an aryl or aheteroaryl and Q is —O—, —CF—, —CH(OH)— or —C(CH₃)₂—. In otherembodiments, the ring system denoted by “A” is an aryl or a heteroaryland Q is —O—, —OCH₂— or —OCH₂CH₂—.

In another embodiment of the presently disclosed compounds of formulae(I)-(VIII) as described above, the ring system denoted by “A” is aheterocycloalkyl. For example, in certain embodiments, the ring systemdenoted by “A” is a tetrahydro-2H-pyranyl or a morpholino. In one suchembodiment, when the “A” ring system is a heterocycloalkyl, Q is asingle bond. In another such embodiment, Q is —CH₂— or —C(O)—. Inanother such embodiment, Q is —O—, —OCH₂— or —OCH₂CH₂—.

In another embodiment of the presently disclosed compounds of formulae(I)-(VIII) as described above, the ring system denoted by “A” is acycloalkyl. For example, in certain embodiments, the ring system denotedby “A” is a cyclohexyl. In one such embodiment, when the “A” ring systemis a cycloalkyl, Q is —CH₂— or —C(O)—. In another such embodiment, Q isa single bond. In another such embodiment, Q is —O—, —OCH₂— or—OCH₂CH₂—.

In certain embodiments of the compounds of formulae (I)-(VIII) asdescribed above, T is H, —(C₁-C₆ alkyl) or —C(O)(C₁-C₆ alkyl). Incertain such embodiments, the alkyl moieties of T are unsubstituted. Inother such embodiments, the alkyl moieties of T are optionallysubstituted as described below. For example, in certain embodiments, Tis H, ispropropyl, or —C(O)-t-butyl.

In certain embodiments of the compounds of formulae (I)-(VIII) asdescribed above, T is —C(CH₃)₂Ar, —CH₂-Het, -Het, —CH₂-Cak or -Hca. The—Ar, -Het, -Cak and -Hca moieties can, for example, be substituted withy R⁵ moieties, as described above with reference to the ring systemdenoted by “A”.

In certain embodiments of the presently disclosed compounds ofstructural formulae (I)-(VIII) as described above, the T moiety isselected from the group consisting of

monocyclic heterocycloalkyl (for example, tetrahydropyranyl,morpholinyl, piperidinyl, piperazinyl) substituted with 0, 1 or 2 R³⁰,monocyclic heteroaryl (for example, pyridyl, isoxazolyl, oxazolyl,pyrrolyl, thienyl) substituted with 0, 1 or 2 R³⁰; monocyclicheteroarylmethyl- (for example, pyridylmethyl, isoxazolylmethyl,oxazolylmethyl, pyrrolylmethyl, thienylmethyl), in which the heteroarylis substituted with 0, 1 or 2 R³⁰; or monocyclic heteroaryloxy- (forexample, pyridyloxy, isoxazolyloxy, oxazolyloxy, pyrrolyloxy,thienyloxy), in which the heteroaryl is substituted with 0, 1 or 2 R³⁰;in which each R³⁰ is independently selected from halogen (e.g., F, Cl),unsubstituted (C₁-C₆ alkoxy) (e.g., methoxy, ethoxy), —(C₁-C₆haloalkoxy) (e.g., trifluoromethoxy), —SH, —S(unsubstituted C₁-C₆alkyl), —S(C₁-C₆ haloalkyl), —OH, —CN, —NO₂, —NH₂, —NH(unsubstitutedC₁-C₄ alkyl), —N(unsubstituted C₁-C₄ alkyl)₂, —N₃, —SF₅, —C(O)—NH₂,C(O)NH(unsubstituted C₁-C₄ alkyl), C(O)N(unsubstituted C₁-C₄ alkyl)₂,—C(O)OH, C(O)O(unsubstituted C₁-C₆ alkyl), —(NH)₀₋₁SO₂R³³,—(NH)₀₋₁COR³³, heterocycloalkyl optionally substituted with an(unsubstituted C₁-C₆ alkyl) and heteroaryl optionally substituted withan (unsubstituted C₁-C₆ alkyl), in which each R³³ is (unsubstitutedC₁-C₆ alkyl), (C₁-C₆ haloalkyl(unsubstituted C₃-C₈ cycloalkyl) or (C₃-C₈heterocycloalkyl) optionally substituted with an (unsubstituted C₁-C₆alkyl). In certain embodiments, no R³⁰ is substituted on the ring of theT moiety. In other embodiments, one R³⁰ is substituted on the ring ofthe T moiety, for example, at a para-position of a phenyl, ameta-position of a phenyl, or at a 3- or 4-position of a heteroaryl orheterocycloalkyl (as counted from the attachment point of the ringsystem denoted by “B”). Certain particular identities of the T moietywill be found by the person of skill in the art in the compoundsdescribed below with respect to Table 1. Those of skill in the art willunderstand that combinations of such T moieties with othersubcombinations of features disclosed herein is specificallycontemplated.

For example, in certain embodiments of the compounds of formulae(I)-(VIII) as

described above, the T moiety is selected fromheterocycloalkyl optionally substituted by alkyl and/or halogen,-Q-heteroaryl optionally substituted by unsubstituted (C₁-C₄ alkyl)and/or halogen, H, C(O)tBu and isopropyl, in which each X isindependently F, Cl or Br (preferably F or Cl), each R³³ isunsubstituted (C₁-C₄ alkyl), unsubstituted (C₁-C₄ haloalkyl) orcycloalkyl optionally substituted with unsubstituted alkyl,unsubstituted (C₁-C₄ alkyl), unsubstituted (C₁-C₄ haloalkyl) orcycloalkyl optionally substituted with unsubstituted alkyl, and each R³⁵is heterocycloalkyl, optionally substituted with unsubstituted alkyl. Incertain such embodiments, Q is a single bond, —CH₂—, —CH₂O—, —OCH₂CH₂—,—CH₂CH₂—, —O—, —CHF—, —CH(CH₃)—, —C(CH₃)₂—, —CH(OH)—, —CH(COOMe)-,—CH(COOEt)-, —C(O)— or —S(O)₂—.

In one embodiment of the presently disclosed compounds of structuralformulae (I)-(VII) as described above, the compound has structuralformula (IX):

in which the variables are defined as described above with reference toany of structural formulae (I)-(VIII).

In another embodiment of the presently disclosed compounds of structuralformulae (I)-(VIII) as described above, the compound has structuralformula (X):

in which the variables are defined as described above with reference toany of structural formulae (I)-(VIII). For example, in certainembodiments, R² can be

in which the R group is a further substituent, for example, as describedherein.

In another embodiment of the presently disclosed compounds of structuralformulae (I)-(VIII) as described above, the compound has structuralformula (XI):

in which one of X¹, X², X³ and X⁴ are N, and the others are carbons (forexample, independently CH or C substituted with one of the w R³ groups),and all other variables are defined as described above with reference toany of structural formulae (I)-(VIII). For example, in one embodiment,X¹ is N and X², X³ and X⁴ are carbons. In another embodiment, X² is Nand X¹, X³ and X⁴ are carbons. In another embodiment, X³ is N and X¹, X²and X⁴ are carbons. In another embodiment, X⁴ is N and X¹, X² and X³ arecarbons.

In another embodiment of the presently disclosed compounds of structuralformulae (I)-(VIII) as described above, the compound has structuralformula (XII):

in which the variables are defined as described above with reference toany of structural formulae (I)-(VIII).

In another embodiment of the presently disclosed compounds of structuralformulae (I)-(VIII) as described above, the compound has structuralformula (XIII):

in which the variables are defined as described above with reference toany of structural formulae (I)-(VIII).

In the compounds of any of structural formulae (I)-(XIII) as describedabove, w, the number of substituents on the central pyridine,pyridazine, pyrazine or pyrimidine, is 0, 1, 2 or 3. For example, in oneembodiment, w is 0, 1 or 2. In another embodiment, w is 0. In otherembodiments, w is at least 1, and at least one R³ is selected from thegroup consisting of halo, cyano, —(C₁-C₄ fluoroalkyl), —O—(C₁-C₄fluoroalkyl), —C(O)—(C₀-C₄ alkyl), —C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄alkyl)(C₀-C₄ alkyl), —S(O)₂O—(C₀-C₄ alkyl), NO₂ and —C(O)—Hca in whichthe Hca includes a nitrogen atom to which the —C(O)— is bound, in whichno alkyl, fluoroalkyl or heterocycloalkyl is substituted with an aryl,heteroaryl, cycloalkyl or heterocycloalkyl-containing group. Forexample, in certain embodiments, at least one R³ is halo (for example,chloro) or —(C₁-C₄ alkyl) (for example, methyl, ethyl or propyl). Incertain embodiments, an R³ is substituted on the central pyridine,pyrazine, pyridazine or pyrimidine in the meta position relative to theJ moiety.

In certain embodiments of the compounds of any of structural formulae(I)-(XIII) as described above, each R³ is independently selected from—(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl) (for example, difluoromethyl,trifluoromethyl and the like), —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰, —(C₀-C₆alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, in which each R⁷, R⁸ and R¹⁰is independently selected from H, —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl),—(C₀-C₆ alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-NR⁹(C₀-C₆ alkyl), —(C₀-C₆alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-C(O)—(C₀-C₆ alkyl), and —(C₀-C₆alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), and in which no alkyl or haloalkyl issubstituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group. For example, in one embodiment, eachR³ is —(C₁-C₃ alkyl), —(C₁-C₃ haloalkyl), —(C₀-C₃ alkyl)-L-R⁷, —(C₀-C₃alkyl)-NR⁸R⁹, —(C₀-C₃ alkyl)-OR¹⁰, —(C₀-C₃ alkyl)-C(O)R¹⁰, —(C₀-C₃alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, in which each R⁷, R⁸ and R¹⁰is independently selected from H, —(C₁-C₂ alkyl), —(C₁-C₂ haloalkyl),—(C₀-C₂ alkyl)-L-(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-NR⁹(C₀-C₂ alkyl), —(C₀-C₂alkyl)-O—(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-C(O)—(C₀-C₂ alkyl) and —(C₀-C₂alkyl)-S(O)₀₋₂—(C₀-C₂ alkyl), and in which no alkyl or haloalkyl issubstituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group. For example, in certain embodiments,each R³ is halo (for example, chloro) or —(C₁-C₄ alkyl) (for example,methyl, ethyl or propyl). In certain embodiments, each R³ isindependently halogen (e.g., F, Cl), unsubstituted (C₁-C₆ alkoxy) (e.g.,methoxy, ethoxy), —(C₁-C₆ haloalkoxy) (e.g., trifluoromethoxy), —SH,—S(unsubstituted C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —OH, —CN, —NO₂,—NH₂, —NH(unsubstituted C₁-C₄ alkyl), —N(unsubstituted C₁-C₄ alkyl)₂,—N₃, —SF₅, —C(O)—NH₂, C(O)NH(unsubstituted C₁-C₄ alkyl),C(O)N(unsubstituted C₁-C₄ alkyl)₂, —C(O)OH, C(O)O(unsubstituted C₁-C₆alkyl), —(NH)₀₋₁SO₂R³³, —(NH)₀₋₁COR³³, heterocycloalkyl optionallysubstituted with an (unsubstituted C₁-C₆ alkyl) and heteroaryloptionally substituted with an (unsubstituted C₁-C₆ alkyl), in whicheach R³³ is (unsubstituted C₁-C₆ alkyl), (C₁-C₆ haloalkyl(unsubstitutedC₃-C₈ cycloalkyl) or (C₃-C₈ heterocycloalkyl) optionally substitutedwith an (unsubstituted C₁-C₆ alkyl). In certain embodiments, each R³ isindependently methyl, ethyl, n-propyl, isopropyl, trifluoromethyl,pentafluoroethyl, acetyl, —NH₂, —OH, methoxy, ethoxy, trifluoromethoxy,—SO₂Me, -halogen, —NO₂ or —CN.

In certain embodiments of the compounds of any of structural formulae(I)-(XIII) as described above, w is at least one, and at least one R³ is—NR⁸R⁹. For example, in one embodiment, w is 1. In certain suchembodiments, an R³ is substituted on the central pyridine, pyrazine,pyridazine or pyrimidine in the meta position relative to the J moiety.

In other embodiments of the compounds of any of structural formulae(I)-(XIII) as described above, w is at least one, and at least one R³ is—(C₀-C₃ alkyl)-Y¹—(C₁-C₃ alkyl)-Y²—(C₀-C₃ alkyl), in which each of Y¹and Y² is independently L, —O—, —S— or —NR⁹—. For example, in oneembodiment, w is 1. In certain such embodiments, R³ is substituted onthe central pyridine, pyrazine, pyridazine or pyrimidine in the metaposition relative to the J moiety. In one particular embodiment, R³ is—CH₂—N(CH₃)—CH₂—C(O)—OCH₃.

In certain embodiments of the presently disclosed compounds ofstructural formulae (I)-(XIII) as described above, the compound has thestructural formula (XIV):

in which E¹ is absent, —C(O)—, —C(O)NR¹— or —NR¹C(O)—; z is 0 or 1; Y³is N, C or CH and Y⁴ is N, C or CH; Q and G are each independently asingle bond, —CH₂—, —C(H)(R¹⁶)—, —C(R¹⁶)₂—, —CH₂CH₂—, L (for example,—C(O)—NR⁹— or —NR⁹—C(O)—), -L-C(R¹⁶)₂—, —O—(C₀-C₃ alkyl)- in which the(C₀-C₃ alkyl) is bound to the R¹⁷ moiety or the ring system denoted by“A”, or —S(O)₂—; v is 0, 1, 2, 3 or 4; each R¹⁵ is independentlyselected from —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl), —(C₀-C₆ alkyl)-Ar,—(C₀-C₆ alkyl)-Het, —(C₀-C₆ alkyl)-Cak, —(C₀-C₆ alkyl)-Hca, —(C₀-C₆alkyl)-L-R⁷, —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, andtwo R¹⁵ on the same carbon optionally combine to form oxo; and R¹⁷ isHet or Ar, and all other variables are defined as described above withreference to any of structural formula (I)-(XIII).

In certain embodiments of the presently disclosed compounds ofstructural formula (XIV) as described above (for example, those in whichE¹ is —C(O)— or absent, Y³ is N and Y⁴ is N. In other embodiments, (forexample, those in which E¹ is —C(O)—NR¹—), Y³ is C or CH and Y⁴ is N. Inother embodiments, Y³ is N and Y⁴ is C or CH. In other embodiments, Y³is C or CH and Y⁴ is C or CH; in such embodiments, the E¹ and G moietiescan be disposed, for example, cis to one another on the cycloalkyl ring.In certain embodiments of the presently disclosed compounds ofstructural formula (XIV) as described above, z is 1. In otherembodiments, z is 0.

In certain embodiments of the presently disclosed compounds ofstructural formulae (I)-(XIV) as described above, D¹, D² and D³ are allCH or C substituted by one of the w R³, and the R² moiety is anoptionally-substituted piperidine. For example, in one embodiment, acompound has structural formula (XV):

in which all variables are and all as described above with respect toany of structural formulae (I)-(XIV). In one such embodiment, v is 0.

In other embodiments of compounds according to structural formula (XV),one of the R¹⁵ is F. For example, the F can be substituted at the carbonalpha to the E¹ moiety. Accordingly, in certain embodiments, a compoundhas structural formula (XVI):

in which v is 0, 1, 2 or 3 and all other variables are as describedabove with respect to any of structural formulae (I)-(XIV). In certainsuch embodiments, v is 0. In one embodiment, the E¹ moiety and the F aredisposed in a cis relationship to one another. In other embodiment, theE¹ moeity and the F are disposed in a trans relationship to one another.For example, the compound of structural formula (XVI) can be provided asany of the four diastereomers of structural formulae (XVII)-(XX):

in which v is 0, 1, 2 or 3 (e.g., 0), and all other variables are andall as described above with respect to any of structural formulae(I)-(XVI). Compounds can be provided as mixtures of diastereomers orenantiomers, or in diastereomerically and/or enantiomerically enrichedform. In certain embodiments, the compound is provided in substantiallydiastereomerically pure form, for example, as substantiallydiastereomerically pure cis compound, or diastereomerically pure transcompound. In certain embodiments, a compound is provided insubstantially enantiomerically pure form, for example, as one of thecompounds of structural formulae (XVII)-(XX).

In certain embodiments of the compounds of structural formulae(XV)-(XX), the compound has structural formula (XXI):

in which all variables are as described above with respect to any ofstructural formulae (I)-(XX). For example, the

moiety can be selected from

in which the G-R¹⁷ group is as described herein. Such compounds can beprovided as mixtures of diastereomers or enantiomers, or indiastereomerically and/or enantiomerically enriched form. In certainembodiments, the compound is provided in substantiallydiastereomerically pure form, for example, as substantiallydiastereomerically pure cis compound, or diastereomerically pure transcompound. In certain embodiments, a compound is provided insubstantially enantiomerically pure form.

In the compounds of structural formulae (XV)-(XXI), the regiochemistryaround the central pyridine can be as described with respect to any ofclaims (IX)-(XI). Moreover, the E¹ moiety of any such compounds can beabsent, —C(O)—, —C(O)NR¹— or —NR¹C(O)—. In one such embodiment, acompound of any of structural formula (XV)-(XXI) is of structuralformula (XXII):

in which all variables are as described above with respect to any ofstructural formulae (I)-(XXI). For example, the

moiety can be selected from

in which the G-R¹⁷ group is as described herein.

In certain embodiments of the compounds according to structural formula(XV)-(XXII), the ring denoted by “B” is

In certain such embodiments, Y² is N and Y¹ is CH or C substituted byone of the x R⁴. In other such embodiments, both Y¹ and Y² are N. Forexample, in certain embodiments, compounds according to structuralformulae (XV)-(XXII) have structural formula (XXIII):

in which in which all variables are as described above with respect toany of structural formulae (I)-(XXII). In one embodiment, Y¹ is N. Inanother embodiment, Y¹ is CH, or is C substituted by one of the x R⁴.For example, in certain embodiments, compounds have one of structuralformulae (XXIV)-(XXIX):

in which in which all variables are as described above with respect toany of structural formulae (I)-(XXII). In certain embodiments of thecompounds of structural formulae (XXIV)-(XXIX), Y¹ is CH or Csubstituted by one of the x R⁴. In certain embodiments of the compoundsof structural formulae (XXIV)-(XXIX), w is 0. In other such embodiments,x is 0. In still other such embodiments, both w and x are 0. In any suchembodiments, R¹ can be, for example, H, or unsubstituted (C₁-C₄ alkyl)such as methyl. Compounds according to structural formulae (XXVI)-(XXIX)can be provided as mixtures of diastereomers or enantiomers, or indiastereomerically and/or enantiomerically enriched form. In certainembodiments, the compound is provided in substantiallydiastereomerically pure form, for example, as substantiallydiastereomerically pure cis compound, or diastereomerically pure transcompound. In certain embodiments, a compound is provided insubstantially enantiomerically pure form.

In the compounds of structural formulae (XV)-(XXIX) as described above,G and Q can be as described above with reference to structural formulae(I)-(XIV). For example, in certain embodiments, G is CH₂, CO, or SO₂. Incertain embodiments, Q is CH₂, CO, SO₂ or O.

In the compounds of structural formulae (XV)-(XXIX) as described above,R¹⁷ and T can be as described above with reference to structuralformulae (I)-(XIV). For example, in certain embodiments, R¹⁷ is anoptionally substituted phenyl, for example, substituted with 0-2 R³⁰groups as described above. In other embodiments, R¹⁷ is an optionallysubstituted heteroaryl, for example, substituted with 0-2 R³⁰ groups asdescribed above. In certain embodiments, T is

in which Q is as described above. The ring system denoted by A and itsoptional R⁵ substituents can be, for example, phenyl substituted by 0-2R³⁰ groups as described above. In other embodiments, ring system denotedby A and its optional R⁵ substituents are heteroaryl, for example,substituted with 0-2 R³⁰ groups as described above.

As examples, in certain embodiments, the compounds have one ofstructural formulae (XXX)-(XXXV):

in which Q, G, R¹ and R³⁰ are as described above with reference tostructural formulae (I)-(XXIX). In certain such embodiments, R¹ is H. Incertain embodiments, G is CH₂, CO, or SO₂. In certain embodiments, Q isCH₂, CO, SO₂ or O. Compounds according to structural formulae(XXX)-(XXXV) can be provided as mixtures of diastereomers orenantiomers, or in diastereomerically and/or enantiomerically enrichedform. In certain embodiments, the compound is provided in substantiallydiastereomerically pure form, for example, as substantiallydiastereomerically pure cis compound, or diastereomerically pure transcompound. In certain embodiments, a compound is provided insubstantially enantiomerically pure form.

In other embodiments of the presently disclosed compounds of structuralformulae (I)-(XIII) as described above, the compound has the structuralformula (XXXVI):

in which the ring system denoted by “C” is a monocyclic arylene orheteroarylene, or a monocyclic arylene fused to a heterocycloalkyl, andall other variables are as defined above with respect to any ofstructural formulae (I)-(XIV). For example, in certain embodiments, thering system denoted by “C” is a phenylene, for example, a 1,4-phenylene.In other embodiments, the ring system denoted by “C” is a monocyclicheteroarylene, such as a pyridylene (for example, a 2,5-pyridylene); a1,3-pyrazolylene (for example, a 1,3-pyrazolylene); a furanylene (forexample, a 2,4-furanylene); or a thienylene (for example, a2,4-thienylene). In other embodiments, the ring system denoted by “C” isa 1,2,3,4-tetrahydroisoquinolinylene (for example, a1,2,3,4-tetrahydroisoquinolin-2,6-ylene).

In other embodiments of the presently disclosed compounds of structuralformulae (I)-(XIII) as described above, the compound has the structuralformula (XVI):

in which z1 is 0 or 1; z2 is 0 or 1; Y⁵ is N, C or CH; Y⁶ is N, C or CH;each of the v R¹⁵ can be disposed either spiro-fused ring; and all othervariables are as defined above with respect to any of structuralformulae (I)-(XIV).

In certain embodiments of the presently disclosed compounds ofstructural formula (XXXVII) as described above (for example, those inwhich E¹ is —C(O)— or absent), Y⁵ is N and Y⁶ is N. In otherembodiments, (for example, those in which E¹ is —C(O)—NR¹—), Y⁵ is C orCH and Y⁶ is N. In other embodiments, Y⁵ is N and Y⁶ is C or CH. Inother embodiments, Y⁵ is C or CH and Y⁶ is C or CH. In certainembodiments of the presently disclosed compounds of structural formula(XXXVII) as described above, z1 is 1 and z2 is 0. In other embodiments,z1 is 0 and z2 is 1.

In one embodiment of the compounds of structural formula (XIV)-(XXXVII)as described above, Q is a single bond. In another embodiment, Q is—CH₂—. In other embodiments, Q is —C(O)— or —S(O)₂—. In otherembodiments, Q is —NH—C(O)— or —CH₂—NH—C(O)—. In other embodiments, Q is—C(CH₃)₂—, —CH₂CH₂—, —CH(CH₃)—, —CH(OH)— or —CHF—. In other embodiments,Q is —O—. In other embodiments, Q is —CH₂O— or —OCH₂CH₂—. In otherembodiments, Q is —CH(COOMe)- or —CH(COOEt)-.

In one embodiment of the compounds of structural formula (XIV)-(XXXVII)as described above, G is —CH₂—. In other embodiments, G is —C(O)— or—S(O)₂—. In other embodiments, G is —CH(CH₃)— or —C(CH₃)₂—. In otherembodiments, G is —O—. In other embodiments, G is —C(O)—NH— or—C(O)—NH—CH₂—. In other embodiments, G is —CH₂CH₂—. In otherembodiments, G is a single bond. In other embodiments, G is —O—. Inother embodiments, G is —OCH₂— or —CH₂CH₂O—. In other embodiments, G is—CH(COOMe)- or —CH(COOEt)-.

In the presently disclosed compounds of structural formulae(XIV)-(XXXVII) as described above, the above-described Q and G moietiescan be combined in any possible combination. For example, in oneembodiment, Q is a single bond and G is —CH₂— or —C(O)—. In anotherembodiment, Q is —CH₂— or —C(O)— and G is a single bond. In yet anotherembodiment, Q is —CH₂— or —C(O)— and G is —CH₂— or —C(O)—.

In certain embodiments of the compounds of structural formulae(XIV)-(XXXVII) as described above, the ring system denoted by “A” isaryl or heteroaryl, as described above. In one embodiment, the ringsystem denoted by “A” is substituted with one or moreelectron-withdrawing groups as described above. In another embodiment,R¹⁷ is substituted with one or more electron-withdrawing groups asdescribed above. In certain embodiments, the ring system denoted by “A”,R¹⁷ or both are not substituted with an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group. In certain embodiments, theazacycloalkyl to which -G-R¹⁷ is bound is a piperidinyl; in otherembodiments, it is a pyrrolidinyl.

In the presently disclosed compounds of structural formulae(XIV)-(XXXVII) as described above, v is 0, 1, 2, 3 or 4. In oneembodiment, v is 0, 1, 2 or 3. For example, v can be 0, or can be 1 or2.

In certain embodiments of the presently disclosed compounds ofstructural formulae (XIV)-(XXXVII) as described above, two R¹⁵ groupscombine to form an oxo. The oxo can be bound, for example, at theposition alpha relative to the nitrogen of an azacycloalkyl ring. Inother embodiments, no two R¹⁵ groups combine to form an oxo.

In certain embodiments of the presently disclosed compounds ofstructural formulae (XIV)-(XXXVII) as described above, v is at least 1(for example, 1) and at least one R¹⁵ is F. In certain embodiments, theF can be, for example, disposed at a position alpha to the E¹ moiety.When the F and E¹ are both disposed on saturated carbons, they can bedisposed in a cis relationship with respect to one another. For example,in certain embodiments, a compound has structural formula (XXXVIII)

in which Y⁴ is N or CH and all variables are defined as described abovewith respect to structural formulae (I)-(XIV). In other embodiments, acompound has structural formula (XXXIX)

in which Y⁴ is N or CH and all variables are defined as described abovewith respect to structural formulae (I)-(XIV). In other embodiments,when the F and E¹ are both disposed on saturated carbons, they can bedisposed in a trans relationship with respect to one another. Forexample, in one embodiment, a compound has structural formula (XL)

in which Y⁴ is N or CH and all variables are defined as described abovewith respect to structural formulae (I)-(XIV). In another embodiment, acompound has structural formula (XLI)

in which Y⁴ is N or CH and all variables are defined as described abovewith respect to structural formulae (I)-(XIV). Compounds according tostructural formulae (XXXVIII)-(XII) can be provided as mixtures ofdiastereomers or enantiomers, or in diastereomerically and/orenantiomerically enriched form. In certain embodiments, the compound isprovided in substantially diastereomerically pure form, for example, assubstantially diastereomerically pure cis compound, ordiastereomerically pure trans compound. In certain embodiments, acompound is provided in substantially enantiomerically pure form.

In certain embodiments of the presently disclosed compounds ofstructural formulae (XIV)-(XLI) as described above, when v is 4, not allfour R¹⁵ moieties are (C₁-C₆ alkyl).

In certain embodiments of the presently disclosed compounds ofstructural formulae (XIV)-(XLI) as described above, each R¹⁵ isindependently selected from —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl) (forexample, difluoromethyl, trifluoromethyl and the like), —(C₀-C₆alkyl)-L-R⁷, —(C₀-C₆ alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆alkyl)-C(O)R¹⁰, —(C₀-C₆ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN andtwo R¹⁵ on the same carbon optionally combine to form oxo, in which eachR⁷, R⁸ and R¹⁰ is independently selected from H, —(C₁-C₆ alkyl), —(C₁-C₆haloalkyl), —(C₀-C₆ alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-NR⁹(C₀-C₆alkyl), —(C₀-C₆ alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-C(O)—(C₀-C₆alkyl) and —(C₀-C₆ alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), and in which no alkylor haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group. For example, in one embodiment, eachR¹⁵ is —(C₁-C₃ alkyl), —(C₁-C₃ haloalkyl), —(C₀-C₃ alkyl)-L-R⁷, —(C₀-C₃alkyl)-NR⁸R⁹, —(C₀-C₃ alkyl)-OR¹⁰, —(C₀-C₃ alkyl)-C(O)R¹⁰, —(C₀-C₃alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN and two R¹⁵ on the same carbonoptionally combine to form oxo, in which each R⁷, R⁸ and R¹⁰ isindependently selected from H, —(C₁-C₂ alkyl), —(C₁-C₂ haloalkyl),—(C₀-C₂ alkyl)-L-(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-NR⁹(C₀-C₂ alkyl), —(C₀-C₂alkyl)-O—(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-C(O)—(C₀-C₂ alkyl) and —(C₀-C₂alkyl)-S(O)₀₋₂—(C₀-C₂ alkyl), and in which no alkyl or haloalkyl issubstituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group. In certain embodiments, each R¹⁵ isindependently halogen (e.g., F, Cl), unsubstituted (C₁-C₆ alkoxy) (e.g.,methoxy, ethoxy), —(C₁-C₆ haloalkoxy) (e.g., trifluoromethoxy), —SH,—S(unsubstituted C₁-C₆ alkyl), —S(C₁-C₆ haloalkyl), —OH, —CN, —NO₂,—NH₂, —NH(unsubstituted C₁-C₄ alkyl), —N(unsubstituted C₁-C₄ alkyl)₂,—N₃, —SF₅, —C(O)—NH₂, C(O)NH(unsubstituted C₁-C₄ alkyl),C(O)N(unsubstituted C₁-C₄ alkyl)₂, —C(O)OH, C(O)O(unsubstituted C₁-C₆alkyl), —(NH)₀₋₁SO₂R³³, —(NH)₀₋₁COR³³, heterocycloalkyl optionallysubstituted with an (unsubstituted C₁-C₆ alkyl) and heteroaryloptionally substituted with an (unsubstituted C₁-C₆ alkyl), in whicheach R³³ is (unsubstituted C₁-C₆ alkyl), (C₁-C₆ haloalkyl(unsubstitutedC₃-C₈ cycloalkyl) or (C₃-C₈ heterocycloalkyl) optionally substitutedwith an (unsubstituted C₁-C₆ alkyl), and two R₄ optionally come togetherto form oxo. In certain embodiments, each R¹⁵ is independently methyl,ethyl, n-propyl, isopropyl, trifluoromethyl, pentafluoroethyl, acetyl,—NH₂, —OH, methoxy, ethoxy, trifluoromethoxy, —SO₂Me, -halogen, —NO₂,N₃, —SF₅, or —CN, and two R¹⁵ on the same carbon optionally combine toform oxo. In some embodiments, one R¹⁵ is —C(O)NR⁹R⁷, which can bebound, for example, at a position alpha relative to the piperidinenitrogen, or at the position linked to the E¹ moiety.

In certain embodiments of the presently disclosed compounds ofstructural formulae (XIV)-(XLI) as described above, R¹⁷ is anunsubstituted aryl or heteroaryl. In other embodiments, the R¹⁷Ar or Hetis substituted with 1, 2 or 3 substituents independently selected from—(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl) (for example, difluoromethyl,trifluoromethyl and the like), —(C₀-C₆ alkyl)-L-R⁷, —(C₀-C₆alkyl)-NR⁸R⁹, —(C₀-C₆ alkyl)-OR¹⁰, —(C₀-C₆ alkyl)-C(O)R¹⁰, —(C₀-C₆alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, in which each R⁷, R⁸ and R¹⁰is independently selected from H, —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl),—(C₀-C₆ alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-NR⁹(C₀-C₆ alkyl), —(C₀-C₆alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-C(O)—(C₀-C₆ alkyl) and —(C₀-C₆alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), and in which no alkyl or haloalkyl issubstituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group. For example, in one embodiment, theR¹⁷Ar or Het is substituted with 1, 2 or 3 substituents independentlyselected from —(C₁-C₃ alkyl), —(C₁-C₃ haloalkyl), —(C₀-C₃ alkyl)-L-R⁷,—(C₀-C₃ alkyl)-NR⁸R⁹, —(C₀-C₃ alkyl)-OR¹⁰, —(C₀-C₃ alkyl)-C(O)R¹⁰,—(C₀-C₃ alkyl)-S(O)₀₋₂R¹⁰, -halogen, —NO₂ and —CN, in which each R⁷, R⁸and R¹⁰ is independently selected from H, —(C₁-C₂ alkyl), —(C₁-C₂haloalkyl), —(C₀-C₂ alkyl)-L-(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-NR⁹(C₀-C₂alkyl), —(C₀-C₂ alkyl)-O—(C₀-C₂ alkyl), —(C₀-C₂ alkyl)-C(O)—(C₀-C₂alkyl) and —(C₀-C₂ alkyl)-S(O)₀₋₂—(C₀-C₂ alkyl), and in which no alkylor haloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group. In certain embodiments, R¹⁷ issubstituted with 1, 2 or 3 substituents selected from halo, cyano,—(C₁-C₄ haloalkyl), —O—(C₁-C₄ haloalkyl), —(C₁-C₄ alkyl), —O—(C₁-C₄alkyl), —C(O)—(C₀-C₄ alkyl), —C(O)O—(C₀-C₄ alkyl), —C(O)N(C₀-C₄alkyl)(C₀-C₄ alkyl), NO₂ and —C(O)—Hca in which no alkyl or haloalkyl issubstituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group. In certain embodiments, R¹⁷ issubstituted with 1, 2 or 3 substituents selected from halogen (e.g., F,Cl), unsubstituted (C₁-C₆ alkoxy) (e.g., methoxy, ethoxy), —(C₁-C₆haloalkoxy) (e.g., trifluoromethoxy), —SH, —S(unsubstituted C₁-C₆alkyl), —S(C₁-C₆ haloalkyl), —OH, —CN, —NO₂, —NH₂, —NH(unsubstitutedC₁-C₄ alkyl), —N(unsubstituted C₁-C₄ alkyl)₂, —N₃, —SF₅, —C(O)—NH₂,C(O)NH(unsubstituted C₁-C₄ alkyl), C(O)N(unsubstituted C₁-C₄ alkyl)₂,—C(O)OH, C(O)O(unsubstituted C₁-C₆ alkyl), —(NH)₀₋₁SO₂R³³,—(NH)₀₋₁COR³³, heterocycloalkyl optionally substituted with an(unsubstituted C₁-C₆ alkyl) and heteroaryl optionally substituted withan (unsubstituted C₁-C₆ alkyl), in which each R³³ is (unsubstitutedC₁-C₆ alkyl), (C₁-C₆ haloalkyl(unsubstituted C₃-C₈ cycloalkyl) or (C₃-C₈heterocycloalkyl) optionally substituted with an (unsubstituted C₁-C₆alkyl), and two R₄ optionally come together to form oxo. In certainembodiments, each R¹⁷ is substituted with 1, 2 or 3 substituentsselected from methyl, ethyl, n-propyl, isopropyl, trifluoromethyl,pentafluoroethyl, acetyl, —NH₂, —OH, methoxy, ethoxy, trifluoromethoxy,—SO₂Me, -halogen, —NO₂, N₃, —SF₅, or —CN. R¹⁷ can be substituted with,for example, one such substituent, or two such substituents.

In certain embodiments of the presently disclosed compounds ofstructural formulae (XIV)-(XLI) as described above, at least one of R¹⁷and the ring system denoted by “A” is substituted with —C(O)NR²⁷R²⁹, inwhich R²⁷ is selected from H, —(C₁-C₆ alkyl), —(C₁-C₆ haloalkyl) (forexample, difluoromethyl, trifluoromethyl and the like), —(C₀-C₆alkyl)-L-(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-NR⁹(C₀-C₆ alkyl), —(C₀-C₆alkyl)-O—(C₀-C₆ alkyl), —(C₀-C₆ alkyl)-C(O)—(C₀-C₆ alkyl)-(C₀-C₆alkyl)-S(O)₀₋₂—(C₀-C₆ alkyl), in which no heterocycloalkyl, alkyl orhaloalkyl is substituted with an aryl-, heteroaryl-, cycloalkyl- orheterocycloalkyl-containing group, and R²⁹ is —H, —(C₁-C₄ alkyl),—C(O)—(C₁-C₄ alkyl) or —C(O)—O—(C₁-C₄ alkyl) in which no (C₁-C₄ alkyl)is substituted by an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group, or R²⁷ and R²⁹ together with thenitrogen to which they are bound form Hca (for example, morpholino,piperazinyl, pyrrolidinyl or piperidinyl). In certain embodiments,heterocycloalkyl, alkyl or haloalkyl groups of R²⁷ and R²⁹ aresubstituted with 1, 2 or 3 substituents selected from halogen (e.g., F,Cl), unsubstituted (C₁-C₆ alkoxy) (e.g., methoxy, ethoxy), —(C₁-C₆haloalkoxy) (e.g., trifluoromethoxy), —SH, —S(unsubstituted C₁-C₆alkyl), —S(C₁-C₆ haloalkyl), —OH, —CN, —NO₂, —NH₂, —NH(unsubstitutedC₁-C₄ alkyl), —N(unsubstituted C₁-C₄ alkyl)₂, —N₃, —SF₅, —C(O)—NH₂,C(O)NH(unsubstituted C₁-C₄ alkyl), C(O)N(unsubstituted C₁-C₄ alkyl)₂,—C(O)OH, C(O)O(unsubstituted C₁-C₆ alkyl), —(NH)₀₋₁SO₂R³³,—(NH)₀₋₁COR³³, heterocycloalkyl optionally substituted with an(unsubstituted C₁-C₆ alkyl) and heteroaryl optionally substituted withan (unsubstituted C₁-C₆ alkyl), in which each R³³ is (unsubstitutedC₁-C₆ alkyl), (C₁-C₆ haloalkyl(unsubstituted C₃-C₈ cycloalkyl) or (C₃-C₈heterocycloalkyl) optionally substituted with an (unsubstituted C₁-C₆alkyl), and two R₄ optionally come together to form oxo. In certainembodiments, the heterocycloalkyl, alkyl or haloalkyl groups of R²⁷ andR²⁹ are optionally substituted with acetyl, —NH₂, —OH, methoxy, ethoxy,trifluoromethoxy, —SO₂Me, -halogen, —NO₂, N₃, —SF₅, or —CN. In oneembodiment, R²⁷ and R²⁹ are both H. In another embodiment, R²⁷ is CH₃and R²⁹ is H.

In certain embodiments of the presently disclosed compounds ofstructural formulae (XIV)-(XLI) as described above, the -G-R¹⁷ moiety isselected from the group consisting of

monocyclic heterocycloalkyl (for example, tetrahydropyranyl,morpholinyl, piperidinyl, piperazinyl) substituted with 0, 1 or 2 R³⁰,monocyclic heteroaryl (for example, pyridyl, isoxazolyl, oxazolyl,pyrrolyl, thienyl) substituted with 0, 1 or 2 R³⁰; monocyclicheteroarylmethyl- (for example, pyridylmethyl, isoxazolylmethyl,oxazolylmethyl, pyrrolylmethyl, thienylmethyl), in which the heteroarylis substituted with 0, 1 or 2 R³⁰; or monocyclic heteroaryloxy- (forexample, pyridyloxy, isoxazolyloxy, oxazolyloxy, pyrrolyloxy,thienyloxy), in which the heteroaryl is substituted with 0, 1 or 2 R³⁰;in which each R³⁰ is independently selected from halogen (e.g., F, Cl),unsubstituted (C₁-C₆ alkoxy) (e.g., methoxy, ethoxy), —(C₁-C₆haloalkoxy) (e.g., trifluoromethoxy), —SH, —S(unsubstituted C₁-C₆alkyl), —S(C₁-C₆ haloalkyl), —OH, —CN, —NO₂, —NH₂, —NH(unsubstitutedC₁-C₄ alkyl), —N(unsubstituted C₁-C₄ alkyl)₂, —N₃, —SF₅, —C(O)—NH₂,C(O)NH(unsubstituted C₁-C₄ alkyl), C(O)N(unsubstituted C₁-C₄ alkyl)₂,—C(O)OH, C(O)O(unsubstituted C₁-C₆ alkyl), —(NH)₀₋₁SO₂R³³,—(NH)₀₋₁COR³³, heterocycloalkyl optionally substituted with an(unsubstituted C₁-C₆ alkyl) and heteroaryl optionally substituted withan (unsubstituted C₁-C₆ alkyl), in which each R³³ is (unsubstitutedC₁-C₆ alkyl), (C₁-C₆ haloalkyl(unsubstituted C₃-C₈ cycloalkyl) or (C₃-C₈heterocycloalkyl) optionally substituted with an (unsubstituted C₁-C₆alkyl). In certain embodiments, no R³⁰ is substituted on the ring ofR¹⁷. In other embodiments, one R³⁰ is substituted on the ring, forexample, at a para-position of a phenyl, a meta-position of a phenyl, orat a 3- or 4-position of a heteroaryl or heterocycloalkyl (as countedfrom the attachment point of the Y⁴, Y⁶ or the ring system denoted by“C”). Certain particular identities of the -G-R¹⁷ moiety will be foundby the person of skill in the art in the compounds described below withrespect to Table 1. Those of skill in the art will understand thatcombinations of such -G-R¹⁷ moieties with other subcombinations offeatures disclosed herein is specifically contemplated.

For example, in certain embodiments of the compounds of formulae(XIV)-(XLI) as described above, the -G-R¹⁷ moiety is selected from

heterocycloalkyl optionally substituted by alkyl and/or halogen,-Q-heteroaryl optionally substituted by unsubstituted (C₁-C₄ alkyl)and/or halogen, H, C(O)tBu and isopropyl, in which each X isindependently F, Cl or Br (preferably F or Cl), each R³³ isunsubstituted (C₁-C₄ alkyl), unsubstituted (C₁-C₄ haloalkyl) orcycloalkyl optionally substituted with unsubstituted alkyl,unsubstituted (C₁-C₄ alkyl), unsubstituted (C₁-C₄ haloalkyl) orcycloalkyl optionally substituted with unsubstituted alkyl, and each R³⁵is heterocycloalkyl, optionally substituted with unsubstituted alkyl. Incertain such embodiments, Q is a single bond, —CH₂—, —CH₂O—, —OCH₂CH₂—,—CH₂CH₂—, —O—, —CHF—, —CH(CH₃)—, —C(CH₃)₂—, —CH(OH)—, —CH(COOMe)-,—CH(COOEt)-, —C(O)— or —S(O)₂—. As the person of skill in the art willappreciate, the

moiety and G-R¹⁷ moieties described above can be combined in virtuallyany combination, and such combinations are specifically contemplated bythis disclosure. For example, in certain embodiments of the presentlydisclosed compounds of structural formulae (XIV)-(XX) as describedabove, both the

moiety and the -G-R¹⁷ moiety are

(for example, 4-fluorobenzyl or 4-cyanobenzyl). In other embodiments,the

moiety is

(for example, 4-fluorobenzyl or 4-cyanobenzyl), and the -G-R¹⁷ moiety is

(for example, 4-methylphenoxy, 4-methoxyphenoxy, 4-chlorophenoxy,4-cyanophenoxy, 4-cyano-2-methoxyphenoxy, 3-methylphenoxy,3-methoxyphenoxy, 3-fluorophenoxy or 3-cyanophenoxy). Of course, theperson of skill in the art will recognize that other combinations of

and -G-R¹⁷ can be used. Such combinations of

and -G-R¹⁷ in combination with other combinations of features describedherein is specifically contemplated by this disclosure.

In certain embodiments, the presently disclosed compounds have thestructural formula (XLII):

in which the variables are independently defined as described above withrespect to structural formulae (I)-(XLI). In certain embodiments of thecompounds of structural formula (XXI), T is H. In certain embodiments ofthe compounds of structural formula (XLII), T is

as described above with respect to structural formulae (I)-(XLI), and-G-R¹⁷ is benzoyl, benzenesulfonyl, phenyl, 1-phenylethyl,1-methyl-1-phenylethyl, —CH(CO(O)(CH₂)₁₋₃H)-phenyl substituted with 0, 1or 2 R³⁰ as described above, or 4-methoxybenzyl, —C(O)—Cak or —CH₂-Cak.In certain embodiments, G-R¹⁷ is as described above with respect tostructural formulae (I)-(XLI), and T is benzoyl, benzenesulfonyl,1-methyl-1-phenylethyl, heterocycloalkyl, heteroarylmethyl or heteroarylsubstituted with 0, 1 or 2 R³⁰ as described above, or3,5-difluorobenzyl, —C(O)—Cak, (C₁-C₆ alkyl)C(O)— or (C₁-C₆ alkyl). Incertain embodiments, Y is N. In other embodiments, Y is CH or Csubstituted by one of the x R⁴.

In certain embodiments, the presently disclosed compounds have thestructural formula (XLIII):

in which the variables are independently defined as described above withrespect to structural formulae (I)-(XLII). In certain embodiments of thecompounds of structural formula (XLIII), T is H. In certain embodimentsof the compounds of structural formula (XLIII), T is

as described above with respect to structural formulae (I)-(XLII), and-G-R¹⁷ is benzoyl, benzenesulfonyl, phenyl, 1-phenylethyl,1-methyl-1-phenylethyl, —CH(CO(O)(CH₂)₁₋₃H)-phenyl substituted with 0, 1or 2 R³⁰ as described above, or 4-methoxybenzyl, —C(O)—Cak or —CH₂-Cak.In certain embodiments, G-R¹⁷ is as described above with respect tostructural formulae (I)-(XLII), and T is benzoyl, benzenesulfonyl,1-methyl-1-phenylethyl, heterocycloalkyl, heteroarylmethyl or heteroarylsubstituted with 0, 1 or 2 R³⁰ as described above, or3,5-difluorobenzyl, —C(O)—Cak, (C₁-C₆ alkyl)C(O)— or (C₁-C₆ alkyl). Incertain embodiments, Y is N. In other embodiments, Y is CH or Csubstituted by one of the x R⁴.

In certain embodiments, the presently disclosed compounds have thestructural formula (XLIV):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH orC substituted by one of the w R³, and all other variables areindependently defined as described above with respect to structuralformulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ areCH or C substituted by one of the w R³. For example, in certainembodiments, T is (C₁-C₆ alkyl). In other embodiments,

In certain embodiments, the T moiety and the G-R¹⁷ moiety areindependently benzyl, 2-phenylethyl or phenyl substituted with 0, 1 or 2R³⁰ as described above. In certain embodiments, Y is N. In otherembodiments, Y is CH or C substituted by one of the x R⁴.

In certain embodiments, the presently disclosed compounds have thestructural formula (XLV):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH orC substituted by one of the w R³, and all other variables areindependently defined as described above with respect to structuralformulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ areCH or C substituted by one of the w R³. For example, in certainembodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl or phenylsubstituted with 0, 1 or 2 R³⁰ as described above. In certainembodiments, the Q and the NR¹³ are substituted para from one another onthe phenylene. In other embodiments, the Q and the NR¹³ are substitutedmeta from one another on the phenylene.

In certain embodiments, the presently disclosed compounds have thestructural formula (XLVI):

in which the ring system denoted by “C” is heteroarylene (for example,monocyclic heteroarylene), one or two of X¹, X², X³ and X⁴ are N, andthe others are CH or C substituted by one of the w R³, and all othervariables are independently defined as described above with respect tostructural formulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³and X⁴ are CH or C substituted by one of the w R³. For example, incertain embodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl or phenylsubstituted with 0, 1 or 2 R³⁰ as described above. In certainembodiments, the ring system denoted by “C” is a pyrazolylene (forexample, a 1,3-pyrazolylene), a pyridylene (for example, a2,5-pyridylene). In certain embodiments, Y is N. In other embodiments, Yis CH or C substituted by one of the x R⁴.

In certain embodiments, the presently disclosed compounds have thestructural formula (XLVII):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH orC substituted by one of the w R³, and all other variables areindependently defined as described above with respect to structuralformulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ areCH or C substituted by one of the w R³. For example, in certainembodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl, phenylmethoxy,—C(O)NHCH₂-phenyl, heteroaryl, or phenyl substituted with 0, 1 or 2 R³⁰as described above. In certain embodiments, the G and the NR¹ aresubstituted para with respect to one another on the phenylene. In otherembodiments, the G and the NR¹ are substituted meta with respect to oneanother on the phenylene. In other embodiments, the G and the NR¹ aresubstituted ortho with respect to one another on the phenylene. Incertain embodiments, Y is N. In other embodiments, Y is CH or Csubstituted by one of the x R⁴.

In certain embodiments, the presently disclosed compounds have thestructural formula (XLVIII):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH orC substituted by one of the w R³; each of the v R¹⁵ can be disposedeither spiro-fused ring; and all other variables are independentlydefined as described above with respect to structural formulae(I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ are CH or Csubstituted by one of the w R³. For example, in certain embodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl or phenylsubstituted with 0, 1 or 2 R³⁰ as described above. In certainembodiments, Y is N. In other embodiments, Y is CH or C substituted byone of the x R⁴.

In certain embodiments, the presently disclosed compounds have thestructural formula (XLIX):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH orC substituted by one of the w R³; each of the v R¹⁵ can be disposedeither spiro-fused ring; and all other variables are independentlydefined as described above with respect to structural formulae(I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ are CH or Csubstituted by one of the w R³. For example, in certain embodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl or phenylsubstituted with 0, 1 or 2 R³⁰ as described above. In certainembodiments, Y is N. In other embodiments, Y is CH or C substituted byone of the x R⁴.

In certain embodiments, the presently disclosed compounds have thestructural formula (L):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH orC substituted by one of the w R³, and all other variables areindependently defined as described above with respect to structuralformulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ areCH or C substituted by one of the w R³. For example, in certainembodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl, phenylmethoxy,—C(O)NHCH₂-phenyl or phenyl substituted with 0, 1 or 2 R³⁰ as describedabove. In certain embodiments, the G and the NR¹ are substituted parawith respect to one another on the phenylene. In other embodiments, theG and the NR¹ are substituted meta with respect to one another on thephenylene. In other embodiments, the G and the NR¹ are substituted orthowith respect to one another on the phenylene. In certain embodiments, Yis N. In other embodiments, Y is CH or C substituted by one of the x R⁴.

In certain embodiments, the presently disclosed compounds have thestructural formula (LI):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH orC substituted by one of the w R³, R³¹ is defined as described above forR³⁰ with respect to the

moiety and all other variables are independently defined as describedabove with respect to structural formulae (I)-(XLIII). In oneembodiment, X¹ is N and X², X³ and X⁴ are CH or C substituted by one ofthe w R³. In certain embodiments, R³¹ is Br. In certain embodiments, the

moiety is benzyl with 0, 1 or 2 R³⁰ as described above. In certainembodiments, the G and the NR¹ are substituted para with respect to oneanother on the phenylene. In other embodiments, the G and the NR¹ aresubstituted meta with respect to one another on the phenylene. In otherembodiments, the G and the NR¹ are substituted ortho with respect to oneanother on the phenylene. In certain embodiments, Y is N. In otherembodiments, Y is CH or C substituted by one of the x R⁴.

In certain embodiments, the presently disclosed compounds have thestructural formula (LII):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH orC substituted by one of the w R³, and all other variables areindependently defined as described above with respect to structuralformulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ areCH or C substituted by one of the w R³. For example, in certainembodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl, phenoxy,phenylmethoxy, —C(O)NHCH₂-phenyl or phenyl substituted with 0, 1 or 2R³⁰ as described above. In certain embodiments, the G and the NR¹ aresubstituted para with respect to one another on the phenylene. In otherembodiments, the G and the NR¹ are substituted meta with respect to oneanother on the phenylene. In other embodiments, the G and the NR¹ aresubstituted ortho with respect to one another on the phenylene. Incertain embodiments, Y is N. In other embodiments, Y is CH or Csubstituted by one of the x R⁴.

In certain embodiments, the presently disclosed compounds have thestructural formula (LIII):

in which one or two of X¹, X², X³ and X⁴ are N; each of the v R¹⁵ can bedisposed either spiro-fused ring; and the others are CH or C substitutedby one of the w R³, and all other variables are independently defined asdescribed above with respect to structural formulae (I)-(XLIII). In oneembodiment, X¹ is N and X², X³ and X⁴ are CH or C substituted by one ofthe w R³. For example, in certain embodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl or phenylsubstituted with 0, 1 or 2 R³⁰ as described above. In certainembodiments, Y is N. In other embodiments, Y is CH or C substituted byone of the x R⁴.

In certain embodiments, the presently disclosed compounds have thestructural formula (LIV):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH orC substituted by one of the w R³, and all other variables areindependently defined as described above with respect to structuralformulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ areCH or C substituted by one of the w R³. For example, in certainembodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl or phenylsubstituted with 0, 1 or 2 R³⁰ as described above. In certainembodiments, Y is N. In other embodiments, Y is CH or C substituted byone of the x R⁴.

In certain embodiments, the presently disclosed compounds have thestructural formula (LV):

in which the ring system denoted by “B” is a heteroarylene, one or twoof X¹, X², X³ and X⁴ are N, and the others are CH or C substituted byone of the w R³, and all other variables are independently defined asdescribed above with respect to structural formulae (I)-(XLIII). In oneembodiment, X¹ is N and X², X³ and X⁴ are CH or C substituted by one ofthe w R³. For example, in certain embodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl or phenylsubstituted with 0, 1 or 2 R³⁰ as described above. In certainembodiments, the ring system denoted by“B” is a pyrazolylene (forexample, a 1,3-pyrazolylene).

In certain embodiments, the presently disclosed compounds have thestructural formula (LVI):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH orC substituted by one of the w R³, and all other variables areindependently defined as described above with respect to structuralformulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ areCH or C substituted by one of the w R³. For example, in certainembodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl or phenylsubstituted with 0, 1 or 2 R³⁰ as described above. In certainembodiments, Y is N. In other embodiments, Y is CH or C substituted byone of the x R⁴.

In certain embodiments, the presently disclosed compounds have thestructural formula (LVII):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH orC substituted by one of the w R³, and all other variables areindependently defined as described above with respect to structuralformulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ areCH or C substituted by one of the w R³. For example, in certainembodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl or phenylsubstituted with 0, 1 or 2 R³⁰ as described above. The NR¹ and G-R¹⁷moieites can, for example, be substituted cis with respect to oneanother on the cyclohexane ring. In other embodiments, the NR¹ and G-R¹⁷moieites are substituted trans with respect to one another on thecyclohexane ring. In certain embodiments, Y is N. In other embodiments,Y is CH or C substituted by one of the x R⁴.

certain embodiments, the presently disclosed compounds have thestructural formula (LVIII):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH orC substituted by one of the w R³, and all other variables areindependently defined as described above with respect to structuralformulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ areCH or C substituted by one of the w R³. For example, in certainembodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl, phenoxy or phenylsubstituted with 0, 1 or 2 R³⁰ as described above.

In certain embodiments, the presently disclosed compounds have thestructural formula (LIX):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH orC substituted by one of the w R³, and all other variables areindependently defined as described above with respect to structuralformulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ areCH or C substituted by one of the w R³. For example, in certainembodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl, 2-phenylethyl orphenyl substituted with 0, 1 or 2 R³⁰ as described above. In certainembodiments, Y is N. In other embodiments, Y is CH or C substituted byone of the x R⁴.

In certain embodiments, the presently disclosed compounds have thestructural formula (LX):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH orC substituted by one of the w R³, and all other variables areindependently defined as described above with respect to structuralformulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ areCH or C substituted by one of the w R³. For example, in certainembodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl or phenylsubstituted with 0, 1 or 2 R³⁰ as described above.

In certain embodiments, the presently disclosed compounds have thestructural formula (LXI):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH orC substituted by one of the w R³, and all other variables areindependently defined as described above with respect to structuralformulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ areCH or C substituted by one of the w R³. For example, in certainembodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl or phenylsubstituted with 0, 1 or 2 R³⁰ as described above. In certainembodiments, Y is N. In other embodiments, Y is CH or C substituted byone of the x R⁴.

In certain embodiments, the presently disclosed compounds have thestructural formula (LXII):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH orC substituted by one of the w R³, and all other variables areindependently defined as described above with respect to structuralformulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ areCH or C substituted by one of the w R³. In certain embodiments, thefluorine atom and the —NR¹— are disposed cis with respect to one anotheron the piperidine. In certain embodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl or phenylsubstituted with 0, 1 or 2 R³⁰ as described above. In certainembodiments, Y is N. In other embodiments, Y is CH or C substituted byone of the x R⁴.

In certain embodiments, the presently disclosed compounds have thestructural formula (LXIII):

in which R³² is —H, —(C₁-C₄ alkyl), —C(O)—(C₁-C₄ alkyl) or —C(O)O—(C₁-C₄alkyl), one or two of X¹, X², X³ and X⁴ are N, and the others are CH orC substituted by one of the w R³, and all other variables areindependently defined as described above with respect to structuralformulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ areCH or C substituted by one of the w R³. and the other variables areindependently defined as described above with respect to structuralformulae (I)-(XIV). In certain embodiments, R³² is H or methyl. Incertain embodiments, the fluorine atom and the —NR¹— are disposed ciswith respect to one another on the piperidine. In certain embodiments,the

moiety and the G-R¹⁷ moiety are independently benzyl or phenylsubstituted with 0, 1 or 2 R³⁰ as described above. In certainembodiments, Y is N. In other embodiments, Y is CH or C substituted byone of the x R⁴.

In certain embodiments, the presently disclosed compounds have thestructural formula (LXIV):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH orC substituted by one of the w R³, and all other variables areindependently defined as described above with respect to structuralformulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ areCH or C substituted by one of the w R³. For example, in certainembodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl, phenoxy or phenylsubstituted with 0, 1 or 2 R³⁰ as described above. In certainembodiments, the Q and the NR¹³ are substituted para from one another onthe phenylene. In other embodiments, the Q and the NR¹³ are substitutedmeta from one another on the phenylene.

In certain embodiments, the presently disclosed compounds have thestructural formula (LXV):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH orC substituted by one of the w R³, and all other variables areindependently defined as described above with respect to structuralformulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ areCH or C substituted by one of the w R³. In certain embodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl or phenylsubstituted with 0, 1 or 2 R³⁰ as described above. In certainembodiments, Y is N. In other embodiments, Y is CH or C substituted byone of the x R⁴.

In certain embodiments, the presently disclosed compounds have thestructural formula (LXVI):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH orC substituted by one of the w R³, and all other variables areindependently defined as described above with respect to structuralformulae (I)-(XLIII), and the G-R¹⁷ moiety is optional. In oneembodiment, X¹ is N and X², X³ and X⁴ are CH or C substituted by one ofthe w R³. For example, in certain embodiments, the G-R¹⁷ moiety isabsent. In certain embodiments, the

moiety and the G-R¹⁷ moiety (if present) are independently benzyl orphenyl substituted with 0, 1 or 2 R³⁰ as described above. In certainembodiments, Y is N. In other embodiments, Y is CH or C substituted byone of the x R⁴.

In certain embodiments, the presently disclosed compounds have thestructural formula (LXVII):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH orC substituted by one of the w R³, and all other variables areindependently defined as described above with respect to structuralformulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ areCH or C substituted by one of the w R³. For example, in certainembodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl or phenylsubstituted with 0, 1 or 2 R³⁰ as described above.

In certain embodiments, the presently disclosed compounds have thestructural formula (LXVIII):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH orC substituted by one of the w R³, and all other variables areindependently defined as described above with respect to structuralformulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ areCH or C substituted by one of the w R³. For example, in certainembodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl or phenylsubstituted with 0, 1 or 2 R³⁰ as described above. In certainembodiments, the stereogenic center indicated by “*” is racemic. Inother embodiments, it is enantiomerically enriched, for example, in the(R)-configuration (i.e., the carbon-NR¹ bond disposed above the plane ofthe page). In other embodiments, it is enantiomerically enriched, forexample, in the (S)-configuration (i.e., the carbon-NR¹ bond disposedbelow the plane of the page). In certain embodiments, Y is N. In otherembodiments, Y is CH or C substituted by one of the x R⁴.

In certain embodiments, the presently disclosed compounds have thestructural formula (LXVIII):

in which the ring system denoted by “B” is a heteroarylene, one or twoof X¹, X², X³ and X⁴ are N, and the others are CH or C substituted byone of the w R³, and all other variables are independently defined asdescribed above with respect to structural formulae (I)-(XLIII). In oneembodiment, X¹ is N and X², X³ and X⁴ are CH or C substituted by one ofthe w R³. For example, in certain embodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl or phenylsubstituted with 0, 1 or 2 R³⁰ as described above. In certainembodiments, the ring system denoted by“B” is a triazolylene (forexample, a 1,2,3-triazol-1,4-ylene).

In certain embodiments, the presently disclosed compounds have thestructural formula (LXIX):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH orC substituted by one of the w R³, and all other variables areindependently defined as described above with respect to structuralformulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ areCH or C substituted by one of the w R³. For example, in certainembodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl or phenylsubstituted with 0, 1 or 2 R³⁰ as described above.

In certain embodiments, the presently disclosed compounds have thestructural formula (LXX):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH orC substituted by one of the w R³, and all other variables areindependently defined as described above with respect to structuralformulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ areCH or C substituted by one of the w R³. For example, in certainembodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl, benzoyl,1-fluoro-1-phenylmethyl, phenoxy or phenyl substituted with 0, 1 or 2R³⁰ as described above. In certain embodiments, the

moiety is bound at the 4-position of the piperidine. In otherembodiments, it is bound at the 3-position of the piperidine. In otherembodiments, it is bound at the 2-position of the piperidine.

In certain embodiments, the presently disclosed compounds have thestructural formula (LXXI):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH orC substituted by one of the w R³, and all other variables areindependently defined as described above with respect to structuralformulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ areCH or C substituted by one of the w R³. For example, in certainembodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl, benzoyl,1-fluoro-1-phenylmethyl, phenoxy or phenyl substituted with 0, 1 or 2R³⁰ as described above.

In certain embodiments, the presently disclosed compounds have thestructural formula (LXXII):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH orC substituted by one of the w R³, and all other variables areindependently defined as described above with respect to structuralformulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ areCH or C substituted by one of the w R³. For example, in certainembodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl or phenylsubstituted with 0, 1 or 2 R³⁰ as described above.

In certain embodiments, the presently disclosed compounds have thestructural formula (LXXIII):

in which one or two of X¹, X², X³ and X⁴ are N and the others are CH orC substituted by one of the w R³; each of the R¹⁵ is substituted oneither ring of the 1,2,3,4-tetrahydroisoquinoline; and all othervariables are independently defined as described above with respect tostructural formulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³and X⁴ are CH or C substituted by one of the w R³. For example, incertain embodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl or phenylsubstituted with 0, 1 or 2 R³⁰ as described above. In certainembodiments, Y is N. In other embodiments, Y is CH or C substituted byone of the x R⁴.

In certain embodiments, the presently disclosed compounds have thestructural formula (LXXIV):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH orC substituted by one of the w R³; each of the R¹⁵ is substituted oneither ring of the 1,2,3,4-tetrahydroisoquinoline; and all othervariables are independently defined as described above with respect tostructural formulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³and X⁴ are CH or C substituted by one of the w R³. For example, incertain embodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl or phenylsubstituted with 0, 1 or 2 R³⁰ as described above.

In certain embodiments, the presently disclosed compounds have thestructural formula (LXXV):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH orC substituted by one of the w R³, and all other variables areindependently defined as described above with respect to structuralformulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ areCH or C substituted by one of the w R³. For example, in certainembodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl or phenylsubstituted with 0, 1 or 2 R³⁰ as described above. In other embodiments,the Q moiety is —O—CH₂—CH₂—.

In certain embodiments, the presently disclosed compounds have thestructural formula (LXXVI):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH orC substituted by one of the w R³, and all other variables areindependently defined as described above with respect to structuralformulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ areCH or C substituted by one of the w R³. For example, in certainembodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl or phenylsubstituted with 0, 1 or 2 R³⁰ as described above. In certainembodiments, the NR¹ and the -G-R¹⁷ are disposed cis with respect to oneanother on the cyclohexane ring. In other embodiments, the NR¹ and the-G-R¹⁷ are disposed trans with respect to one another on the cyclohexanering. In certain embodiments, Y is N. In other embodiments, Y is CH or Csubstituted by one of the x R⁴.

In certain embodiments, the presently disclosed compounds have thestructural formula (LXXVII):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH orC substituted by one of the w R³, and all other variables areindependently defined as described above with respect to structuralformulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ areCH or C substituted by one of the w R³. For example, in certainembodiments, the

moiety and the G-R¹⁷ moiety are independently benzyl, phenoxy or phenylsubstituted with 0, 1 or 2 R³⁰ as described above.

In certain embodiments, the presently disclosed compounds have thestructural formula (LXXVIII):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH orC substituted by one of the w R³, and all other variables areindependently defined as described above with respect to structuralformulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ areCH or C substituted by one of the w R³. The E moiety can be, forexample, as described with reference to any of structural formulae(XIII)-(LXXVIII). For example, in certain embodiments, the

moiety and the E moiety are independently benzyl, phenoxy or phenylsubstituted with 0, 1 or 2 R³⁰ as described above.

In certain embodiments, the presently disclosed compounds have thestructural formula (LXXIX):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH orC substituted by one of the w R³, E² is —CONR¹— (for example, —CONH—) or—NR¹CO— (for example, —NHCO—), and all other variables are independentlydefined as described above with respect to structural formulae(I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ are CH or Csubstituted by one of the w R³. The -G-R¹⁷ moiety can be, for example,as described with reference to any of structural formulae(XIII)-(LXXVIII). Independently, the

moiety can be, for example, as described with reference to any ofstructural formulae (XIII)-(LXXVIII). For example, in certainembodiments, the T moiety and the G-R¹⁷ moiety are independently benzyl,phenoxy or phenyl substituted with 0, 1 or 2 R³⁰ as described above. Inother embodiments, G is O, CH₂, or SO₂.

In certain embodiments, the presently disclosed compounds have thestructural formula (LXXX):

in which two R⁴ on different carbons combine to form a (C₁-C₄ alkylene)bridge, one or two of X¹, X², X³ and X⁴ are N, and the others are CH orC substituted by one of the w R³, and all other variables areindependently defined as described above with respect to structuralformulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ areCH or C substituted by one of the w R³. The E moiety can be, forexample, as described with reference to any of structural formulae(XIII)-(LXXVIII). Independently, the T moiety can be, for example, asdescribed with reference to any of structural formulae (XIII)-(LVII).For example, in certain embodiments, the T moiety is independentlybenzyl, phenoxy or phenyl substituted with 0, 1 or 2 R³⁰ as describedabove. In certain embodiments, Y is N. In other embodiments, Y is CH orC substituted by one of the x R⁴. In certain embodiments, the

moiety is

In certain embodiments, the presently disclosed compounds have thestructural formula (LXXXI):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH orC substituted by one of the w R³, and all other variables areindependently defined as described above with respect to structuralformulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ areCH or C substituted by one of the w R³. In one embodiment, R¹ is H. The—R¹⁷ moiety can be, for example, as described with reference to any ofstructural formulae (XIII)-(LXXVIII). Independently, the

moiety can be, for example, as described with reference to any ofstructural formulae (XIII)-(LXXVIII). For example, in certainembodiments, the T moiety is benzyl, phenoxy or phenyl substituted with0, 1 or 2 R³⁰ as described above; and the R¹⁷ moiety is phenylsubstituted with 0, 1 or 2 R³⁰ as described above.

In certain embodiments, the presently disclosed compounds have thestructural formula (LXXXII):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH orC substituted by one of the w R³, and all other variables areindependently defined as described above with respect to structuralformulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ areCH or C substituted by one of the w R³. The E moiety can be, forexample, as described with reference to any of structural formulae(XIII)-(LXXVIII). Independently, the T moiety can be, for example, asdescribed with reference to any of structural formulae (XIII)-(LXXVIII).For example, in certain embodiments, the T moiety is benzyl, phenoxy orphenyl substituted with 0, 1 or 2 R³⁰ as described above.

In certain embodiments, the presently disclosed compounds have thestructural formula (LXXXIII):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH orC substituted by one of the w R³, and all other variables areindependently defined as described above with respect to structuralformulae (I)-(XLIII). In one embodiment, X¹ is N and X², X³ and X⁴ areCH or C substituted by one of the w R³. The E moiety can be, forexample, as described with reference to any of structural formulae(XIII)-(LXXVIII). The A-(R⁵)_(y) moiety independently be, for example,described reference to any of structural formulae (XIII)-(LXXVIII). Forexample, in certain embodiments, the T moiety is benzyl, phenoxy orphenyl substituted with 0, 1 or 2 R³⁰ as described above.

In certain embodiments, the presently disclosed compounds have thestructural formula (LXXXIV):

in which one or two of X¹, X², X³ and X⁴ are N, and the others are CH orC substituted by one of the w R³, and all other variables areindependently defined as described above with respect to structuralformulae (I)-(XXII). In one embodiment, X¹ is N and X², X³ and X⁴ are CHor C substituted by one of the w R³. In one embodiment, R¹ is H. The-G-R¹⁷ moiety can be, for example, as described with reference to any ofstructural formulae (XIII)-(LXXVIII). Independently, the

moiety can be, for example, as described with reference to any ofstructural formulae (XIII)-(LXXVIII). For example, in certainembodiments, the T moiety is benzyl, phenoxy or phenyl substituted with0, 1 or 2 R³⁰ as described above; and the R¹⁷ moiety is phenylsubstituted with 0, 1 or 2 R³⁰ as described above.

In certain embodiments of compounds having structural formulae(XIII)-(LXXVIII), the

moiety is p-(trifluoromethyl)phenyl, p-fluorophenoxy,m-chloro-p-cyanophenoxy, p-trifluoromethylphenoxy, m,p-difluorophenoxy,m-cyanophenoxy, p-chlorobenzoyl, 2-(p-fluorophenoxy)ethyl,m-methoxyphenyl, m-fluoro-p-methoxybenzyl, p-methylbenzyl,α,p-difluorobenzyl, p-fluoro-α-hydroxybenzyl, 1-methyl-1-phenylethyl,p-chlorophenyl, p-cyanophenoxy, benzenesulfonyl,tetrahydro-2H-pyran-4-yl, 5-methylisoxazol-3-yl,p-fluorobenzenesulfonyl, p-methoxybenzenesulfonyl, benzyl,p-cyano-o-methoxyphenoxy, p-methoxybenzoyl, p-methoxyphenoxy, benzoyl,p-fluorobenzoyl, cyclohexanecarbonyl, p-methoxybenzoyl,cyclohexylmethyl, pyrid-4-yl, pyrid-4-ylmethyl, phenoxy, phenyl,phenethyl, p-methoxyphenyl, p-fluorophenyl, p-cyanophenyl,p-(trifluoromethyl)benzyl, p-methoxybenzyl, p-fluorobenzyl,m,m-difluorobenzyl, p-carbamoylbenzyl, p-(pentafluorosulfanyl)benzyl,p-(pentafluorosulfanyl)phenoxy, p-(cyclopropylsulfonyl)phenoxy,p-(cyclopropylsulfonyl)benzyl, p-(methylsulfonyl)benzyl,p-(methylsulfonyl)phenoxy, p-(trifluoromethylsulfonyl)phenoxy,p-(trifluoromethylsulfonyl)phenyl, p-(methylsulfonyl)phenyl,p-(dimethylcarbamoyl)benzyl, p-(isopropylsulfonyl)phenyl,p-(cyclopropylsulfonyl)phenyl, p-azidobenzoyl, o,p-difluorobenzoyl,o,p-difluorobenzoxy, pyridin-3-yloxy, pyridin-4-yloxy,m,p-difluorobenzoyl, p-fluorobenzyloxy, p-(1-pyrrolidinyl)benzyol,p-(trifluoromethylthio)phenoxy, m-(cyclopropanecarboxamido)phenoxy,p-acetamidophenoxy, m-acetamidophenoxy, p-cyclopropancarboxamidphenoxy,p-morpholinobenzoyl, p-(4-methylpiperzine-1-yl)benzoyl,p-methoxy-o-nitrophenoxy, p-(methylsulfinyl)benzoyl,p-(methylsulfonamido)benzoxy, p-nitrophenoxy, p-aminophenoxy orp-cyanobenzyl.

Another aspect of the disclosure provides compounds of structuralformula (LXXXV):

in which each of the variables is independently defined as describedabove with respect to structural formulae (I)-(LXXXIV). For example, incertain embodiments, a compound has structural formula (LXXXVI):

in which each of the variables is independently defined as describedabove with respect to structural formulae (I)-(LXXVIII).

In certain embodiments of compounds having structural formulae(XIII)-(LXXVI) as described above, the -G-R¹⁷ moiety is p-chlorobenzyl,p-fluorobenzyl, p-cyanobenzyl, p-cyano-m-fluorobenzyl, p-cyanobenzoyl,p-cyanobenzenesulfonyl, cyclohexanecarbonyl, benzoyl, benzyl, phenyl,cyclohexylmethyl, phenoxy, phenylmethoxy, 1-phenylethyl, p-nitrophenyl,cyanophenyl, p-(trifluoromethyl)phenyl, p-bromophenyl, 1H-pyrrol-3-yl,4-morpholinyl, 4-methylpiperazin-1-yl, p-cyanobenzylcarbamoyl,m,m-difluorobenzyl, p-fluoro-m-methylbenzyl, p-methoxybenzyl,p-chlorobenzyl, p-methylbenzoxy, m-fluorophenoxy, p-fluorophenoxy,m-cyanophenoxy, m-methoxyphenoxy, m-methylphenoxy, p-cyanophenoxy,p-fluorophenoxy, pyrid-3-yl, thien-3-yl, phenethyl, α-carboethoxybenzyl,pyrid-4-ylmethyl, 1-(p-cyanophenyl)-1-methylethyl,p-(trifluoromethyl)benzenesulfonyl, p-(trifluoromethyl)phenoxy,p-(trifluoromethyl)benzyl, m-(trifluoromethyl)benzyl,p-methylsulfonylbenxyl, p-methylsulfonylphenoxy, p-acetylphenoxy,p-pyrrolidinylbenzyl, or p-methoxybenzyl,

As the person of skill in the art will recognize, the variousembodiments and features described above can be combined to form otherembodiments contemplated by the disclosure. For example, in oneembodiment of the compounds of certain of structural formulae (I)-(LXXV)as described above, Q is —CH₂—, as described above, and G is —CH₂—, asdescribed above. In another embodiment of the compounds of certain ofstructural formulae (I)-(LXXV) as described above, x is 0 and each w is0. In another embodiment of the compounds of certain of structuralformulae (I)-(LXXVI), x is 0, each w is 0 and each v is 0.

Moreover, the various -E moieties and T-(“B” ring system)-J- moietiesdescribed above with respect to any of structural formulae (I)-(LXXVI)can be combined around the central pyridine, pyrazine, pyridazine orpyrimidine (for example, in any of the ways described with respect tostructural formulae (IX)-(XIII)) to form additional embodiments ofcompounds specifically contemplated by this disclosure.

Examples of compounds according to structural formula (I) include thoselisted in Table 1. These compounds can be made according to the generalschemes described below, for example using procedures analogous to thosedescribed below in the Examples.

TABLE 1 No. Name Structure 1 N-(4-(4-cyanobenzyl)piperadin-4-yl)-6-(4-(4-fluorobenzyl)piperizine-1- carbonyl)picolinamide

2 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(piperazine-1-carbonyl)picolinamide

3 pyridine-2,5-diylbis((4-(4- fluorobenzyl)piperazin-1-yl)methanone)

4 N-(1-(4-cyanobenzoyl)piperidin-4-yl)-5-(4-(4-fluorobenzyl)piperazine-1- carbonyl)picolinamide

5 N²-(1-(4-cyanobenzyl)piperidin-4-yl)-N⁵-(3-benzylphenyl)pyridine-2,5-dicarboxamide

6 N-(4-((4-cyanophenyl)sulfonyl)piperidin-4-yl)-5-(4-(4-fluorobenzyl)piperazine-1- carbonyl)picolinamide

7 N-(1-(cyclohexanecarbonyl)piperidin-4-yl)-5-(4-(4-fluorobenzyl)piperazine-1- carbonyl)picolinamide

8 N-(1-(benzoyl)piperidin-4-yl)-5-(4-(4- fluorobenzyl)piperazine-1-carbonyl)picolinamide

9 N-(1-(4-cyanobenzyl)-1H-pyrazol-3-yl)-5-(4-(4-fluorobenzyl)piperazine-1- carbonyl)picolinamide

10 N-(4-benzylphenyl)-5-(4-(4- fluorobenzyl)piperazine-1-carbonyl)picolinamide

11 5-(4-(4-fluorobenzyl)piperazine-1-carbonyl-N-(4-phenylphenyl)picolinamide

12 5-(4-(4-fluorobenzyl)piperazine-1-carbonyl-N-(3-phenylphenyl)picolinamide

13 N-(1-(cyclohexylmethyl)piperidin-4-yl)-5-(4-(4-fluorobenzyl)piperazine-1- carbonyl)picolinamide

14 5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(1-(phenyl)piperidin-4- yl)picolinamide

15 4-((8-(5-(4-(4-fluorobenzyl)piperazine-1- carbonyl)picolinoyl)-2,8-diazaspiro[4.5]decan-2- yl)methyl)benzonitrile

16 5-(4-(4-fluorobenzyl)piperazine-1- carbonyl)-N-(4-phenoxyphenyl)picolinamide

17 (4-(4-fluorobenzyl)piperazin-1-yl)(6-(4-(benzyloxy)phenyl)pyridin-3-yl)methanone

18 5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(1-(1-phenylethyl)piperidin-4- yl)picolinamide

19 5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(2-phenylphenyl)picolinamide

20 5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(4-(4-nitrophenyl)phenyl) picolinamide

21 5-(4-(4-fluorobenzyl)piperazine-1- carbonyl)-N-(3-phenoxyphenyl)picolinamide

22 (6-(3-(benzyloxy)phenyl)pyridin-3-yl)(4-(4-fluorobenzyl)piperazin-1-yl)methanone

23 N-(1-(4-cyanobenzyl)-1H-pyrazol-4-yl)-5-(4-(4-fluorobenzyl)piperazine-1- carbonyl)picolinamide

24 N-(4-(4-cyanophenyl)phenyl)-5-(4-(4- fluorobenzyl)piperazine-1-carbonyl)picolinamide

25 5-(4-(4-fluorobenzyl)piperazine-1- carbonyl)-N-(4-(4-trifluoromethylphenyl)phenyl)picolinamide

26 N-(4-benzoylphenyl)-5-(4-(4- fluorobenzyl)piperazine-1-carbonyl)picolinamide

27 N-(4-benzyloxyphenyl)-5-(4-(4- fluorobenzyl)piperazine-1-carbonyl)picolinamide

28 N-(4-bromophenyl)-5-(4-(4- fluorobenzyl)piperazine-1-carbonyl)picolinamide

29 N-(4-(4-methoxyphenyl)phenyl)-5-(4-(4- fluorobenzyl)piperazine-1-carbonyl)picolinamide

30 (6-(4-benzylphenylamino)pyridin-3-yl)(4-(4-fluorobenzyl)piperazin-1-yl)methanone

31 4-((2-(5-(4-(4-fluorobenzyl)piperazine-1- carbonyl)pyridin-2-yl)-2,8-diazaspiro[4.5]decan-8- yl)methyl)benzonitrile

32 N-(4-(3-cyanophenyl)phenyl)-5-(4-(4- fluorobenzyl)piperazine-1-carbonyl)picolinamide

33 (6-(3-phenylphenylamino)pyridin-3-yl)(4-(4-fluorobenzyl)piperazin-1-yl)methanone

34 (4-(4-fluorobenzyl)piperazin-1-yl)(6-(4-phenoxyphenylamino)pyridin-3- yl)methanone

35 (6-(4-(4- cyanobenzylcarbamoyl)phenyl)pyridin-3-yl)(4-(4-fluorobenzyl)piperazin-1- yl)methanone

36 (6-(4-(cyanobenzyl)piperidin-4- ylamino)pyridin-3-yl)(4-(4-fluorobenzyl)piperazin-1-yl)methanone

37 (6-(4-phenylphenylamino)pyridin-3-yl)(4-(4-fluorobenzyl)piperazin-1-yl)methanone

38 N⁵-(1-(4-cyanobenzyl)-1H-pyrazol-3-yl)-N²-(1-(4-cyanobenzyl)piperidin-4-yl)pyridine- 2,5-dicarboxamide

39 5-(4-(4-fluorobenzyl)piperazine-1- carbonyl)-N-(4-(1H-pyrrol-3-yl)phenyl)picolinamide

40 5-(4-(4-fluorobenzyl)piperazine-1- carbonyl)-N-(4-morpholinophenyl)picolinamide

41 5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(4-(4-methylpiperazin-1- yl)phenyl)picolinamide

42 (6-(3-(4- cyanobenzylcarbamoyl)phenyl)pyridin-3yl)(4-(4-fluorobenzyl)piperazin-1- yl)methanone

43 N⁵-(1-(4-cyanobenzyl)-1H-pyrazol-4-yl)-N²-(1-(4-cyanobenzyl)piperidin-4-yl)pyridine- 2,5-dicarboxamide

44 (6-(1-(4-fluorobenzyl)-1H-pyrazol-4- ylamino)pyridin-3-yl)(4-(4-fluorobenzyl)piperazin-1-yl)methanone

45 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(1-(4-fluorobenzyl)-1H-pyrazol-4- ylamino)picolinamide

46 (6-(1-(4-cyanobenzyl)piperidine-4- carboxamido)pyridin-3-yl)(4-(4-fluorobenzyl)piperazin-1-yl)methanone

47 N-(4-(4-cyanobenzylcarbamoyl)phenyl)-5-(4-(4-fluorobenzyl)piperazine-1- carbonyl)picolinamide

48 (6-(4-(4- cyanobenzylcarbamoyl)phenylamino)pyridin-3-yl)(4-(4-fluorobenzyl)piperazin-1- yl)methanone

49 N-(1-(3,5-difluorobenzyl)piperidin-4-yl)-5-(4-(4-fluorobenzyl)piperazine-1- carbonyl)picolinamide

50 5-(4-(4-fluorobenzyl)piperazine-1- carbonyl)-N-(1-(4-fluoro-3-methylbenzyl)piperidin-4-yl)picolinamide

51 N-(1-(4-chlorobenzyl)piperidin-4-yl)-5-(4-(4-fluorobenzyl)piperazine-1- carbonyl)picolinamide

52 N-(1-(4-chlorobenzyl)piperidin-4-yl)-5-(4-(4-fluorobenzyl)piperazine-1- carbonyl)picolinamide

53 5-(4-(4-fluorobenzyl)piperazine-1- carbonyl)-N-(4-(4-methylphenoxy)phenyl)picolinamide

54 5-(4-(4-fluorobenzyl)piperazine-1- carbonyl)-N-(4-(4-methoxyphenoxy)phenyl)picolinamide

55 5-(4-(4-fluorobenzyl)piperazine-1- carbonyl)-N-(4-(3-fluorophenoxy)phenyl)picolinamide

56 N-(4-(3-cyanophenoxy)phenyl)-5-(4-(4- fluorobenzyl)piperazine-1-carbonyl)picolinamide

57 5-(4-(4-fluorobenzyl)piperazine-1- carbonyl)-N-(4-(3-methoxyphenoxy)phenyl)picolinamide

58 5-(4-(4-fluorobenzyl)piperazine-1- carbonyl)-N-(4-(3-methylphenoxy)phenyl)picolinamide

59 N-(4-(4-cyanophenoxy)phenyl)-5-(4-(4- fluorobenzyl)piperazine-1-carbonyl)picolinamide

60 5-(4-(4-fluorobenzyl)piperazine-1- carbonyl)-N-(4-(4-fluorophenoxy)phenyl)picolinamide

61 5-(4-(4-fluorobenzyl)piperazine-1- carbonyl)-N-(4-(pyridine-3-yl)phenyl)picolinamide

62 5-(4-(4-fluorobenzyl)piperazine-1- carbonyl)-N-(4-(thiophen-3-yl)phenyl)picolinamide

63 5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-(6-(4-cyanophenoxy)pyridin-3- yl)picolinamide

64 5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-(6-(3-cyanophenoxy)pyridin-3- yl)picolinamide

65 5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3- yl)picolinamide

66 5-(4-(4-cyano-2- methoxyphenoxy)piperidine-1-carbonyl)-N-(1-(4-cyanobenzyl)piperidin-4- yl)picolinamide

67 5-(4-(4-fluoro-4-fluorobenzoyl)piperidine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin- 3-yl)picolinamide

68 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-fluoro-4-fluorobenzoyl)piperidine-1- carbonyl)picolinamide

69 5-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3- yl)picolinamide

70 5-(4-(4-methoxyphenoxy)piperidine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3- yl)picolinamide

71 trans-N-(4-(4-cyanophenoxy)cyclohexyl)-5-(4-(4-fluorobenzyl)piperazine-1- carbonyl)picolinamide

72 5-(4-benzylpiperazine-1-carbonyl)-N-(1-benzylpiperidin-4-yl)picolinamide

73 pyridine-2,5-diylbis((4-benzylpiperazin-1- yl)methanone)

74 6-(4-benzylpiperazine-1-carbonyl)-N-(1-benzylpiperidin-4-yl)nicotinamide

75 5,5′-(piperazine-1,4- diylbis(oxomethylene))bis(N-(1-(4-cyanobenzyl)piperidin-4-yl)picolinamide)

76 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-fluorobenzoyl)piperazine-1- carbonyl)picolinamide

77 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-methoxybenzoyl)piperazine-1- carbonyl)picolinamide

78 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-fluorophenylsulfonyl)piperazine-1- carbonyl)picolinamide

79 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-methoxyphenylsulfonyl)piperazine-1- carbonyl)picolinamide

80 5-(4-benzoylpiperazine-1-carbonyl)-N-(1-(4-cyanobenzyl)piperidin-4-yl)picolinamide

81 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-pivaloylpiperazine-1-carbonyl)picolinamide

82 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(phenylsulfonyl)piperazine-1- carbonyl)picolinamide

83 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(tetrahydro-2H-pyran-4-yl)piperazine-1- carbonyl)picolinamide

84 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4- isopropylpiperazine-1-carbonyl)picolinamide

85 N-(1-benzylpiperidin-4-yl)-5-(4-((5-methylisoxazol-3-yl)methyl)piperazine-1- carbonyl)picolinamide

86 N2,N6-bis(1-(4-cyanobenzyl)piperidin-4- yl)pyridine-2,6-dicarboxamide

87 N2,N6-bis(1-(4-fluorobenzyl)piperidin-4-yl)pyridine-2,6-dicarboxamide

88 (4-(4-fluorobenzyl)piperazin-1-yl)(6-(4-phenethylpiperazine-1-carbonyl)pyridin-3- yl)methanone

89 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(cyclohexanecarbonyl)piperazine-1- carbonyl)picolinamide

90 (4-phenethylpiperazin-1-yl)(5-(4-phenylpiperazine-1-carbonyl)pyridin-2- yl)methanone

91 (4-isopropylpiperazin-1-yl)(6-(4-phenethylpiperazine-1-carbonyl)pyridin-3- yl)methanone

92 pyridine-2,5-diylbis((4-phenethylpiperazin- 1-yl)methanone)

93 (4-(4-fluorobenzyl)piperazin-1-yl)(6-(4-phenethylpiperazine-1-carbonyl)pyridin-2- yl)methanone

94 (4-(4-fluorobenzyl)piperazin-1-yl)(6-(4-phenylpiperazine-1-carbonyl)pyridin-2- yl)methanone

95 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(cyclohexylmethyl)piperazine-1- carbonyl)picolinamide

96 N-(1-benzylpiperidin-4-yl)-5-(4-(pyridin-4-yl)piperazine-1-carbonyl)picolinamide

97 N-(1-benzylpiperidin-4-yl)-5-(4-phenylpiperazine-1-carbonyl)picolinamide

98 ethyl 2-(4-(5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamido)piperidin-1-yl)-2- phenylacetate

99 N-(4-(4-cyanobenzyl)cyclohexyl)-6-(4-(4- fluorobenzyl)piperazine-1-carbonyl)picolinamide

100 cis-1-(4-cyanobenzyl)-3-fluoropiperidin-4-yl)-5-(4-(4-fluorobenzyl)piperazine-1- carbonyl)picolinamide

101 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-methoxybenzyl)piperazine-1- carbonyl)picolinamide

102 5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(cis-3-fluoropiperidin-4- yl)picolinamide

103 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(pyridin-4-ylmethyl)piperazine-1- carbonyl)picolinamide

104 N-(cis-3-fluoro-1-(pyridin-4- ylmethyl)piperidin-4-yl)-5-(4-(4-fluorobenzyl)piperazine-1- carbonyl)picolinamide

105 N2-(1-benzylpiperidin-4-yl)-N5-(biphenyl-4-yl)pyridine-2,5-dicarboxamide

106 N2-(1-benzylpiperidin-4-yl)-N5-(biphenyl-3-yl)pyridine-2,5-dicarboxamide

107 5-(4-(4-fluorobenzyl)piperazine-1- carbonyl)-N-phenylpicolinamide

108 5-(4-benzylphenylamino)-N-(1-(4-cyanobenzyl)piperidin-4-yl)picolinamide

109 5-(biphenyl-4-ylamino)-N-(1-(4-cyanobenzyl)piperidin-4-yl)picolinamide

110 5-(4-benzylpiperazin-1-yl)-N-(1-(4-cyanobenzyl)piperidin-4-yl)picolinamide

111 N-(1-(2-(4-cyanophenyl)propan-2- yl)piperidin-4-yl)-5-(4-(4-fluorobenzyl)piperazine-1- carbonyl)picolinamide

112 N-(1-benzylpiperidin-4-yl)-5-(3- phenoxyphenylamino)picolinamide

113 N-(1-benzylpiperidin-4-yl)-5-(4- phenoxyphenylamino)picolinamide

114 N-(1-benzylpiperidin-4-yl)-5-(biphenyl-3- ylamino)picolinamide

115 N-benzyl-5-(4-(4-fluorobenzyl)piperazine- 1-carbonyl)picolinamide

116 N-benzyl-5-(4-benzylpiperazine-1- carbonyl)picolinamide

117 5-(4-(4-fluorobenzyl)piperazine-1- carbonyl)-N-(1-(4-methoxybenzyl)piperidin-4-yl)picolinamide

118 (R)-N-(1-(4-cyanobenzyl)pyrrolidin-3-yl)-5-(4-(4-fluorobenzyl)piperazine-1- carbonyl)picolinamide

119 N-(1-benzylpiperidin-4-yl)-5-(4′-cyanobiphenyl-4-ylamino)picolinamide

120 N-(1-benzylpiperidin-4-yl)-5-(4′-methoxybiphenyl-4-ylamino)picolinamide

121 5-(1-benzyl-1H-1,2,3-triazol-4-yl)-N-(1-(4-cyanobenzyl)piperidin-4-yl)picolinamide

122 5-(1-benzyl-1H-1,2,3-triazol-4-yl)-N-(1-(4-cyanobenzyl)piperidin-4-yl)picolinamide

123 (S)-N-(1-(4-cyanobenzyl)pyrrolidin-3-yl)-5-(4-(4-fluorobenzyl)piperazine-1- carbonyl)picolinamide

124 5-(4-benzylpiperidine-1-carbonyl)-N-(1-(4-cyanobenzyl)piperidin-4-yl)picolinamide

125 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-fluorobenzyl)-3,3-dimethylpiperazine-1- carbonyl)picolinamide

126 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(1-phenylpiperidin-4-ylamino)picolinamide

127 N-(cis-1-(4-chlorobenzyl)-3- fluoropiperidin-4-yl)-5-(4-(4-fluorobenzyl)piperazine-1- carbonyl)picolinamide

128 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-cyanobenzyl)piperidine-1- carbonyl)picolinamide

129 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-methoxybenzoyl)piperidine-1- carbonyl)picolinamide

130 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-fluorobenzyl)piperidine-1- carbonyl)picolinamide

131 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-methoxybenzyl)piperidine-1- carbonyl)picolinamide

132 N-(2-(4-cyanobenzyl)-1,2,3,4- tetrahydroisoquinolin-7-yl)-5-(4-(4-fluorobenzyl)piperazine-1- carbonyl)picolinamide

133 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(2-phenylpropan-2-yl)piperazine-1- carbonyl)picolinamide

134 5-(4-(4-chlorophenyl)piperidine-1-carbonyl)-N-(1-(4-cyanobenzyl)piperidin-4- yl)picolinamide

135 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-cyanophenoxy)piperidine-1- carbonyl)picolinamide

136 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-fluorobenzoyl)piperidine-1- carbonyl)picolinamide

137 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(3-(4-cyanophenoxy)piperidine-1- carbonyl)picolinamide

138 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(fluoro(4-fluorophenyl)methyl)piperidine-1- carbonyl)picolinamide

139 5-(1-(4-chlorophenyl)piperidin-4-ylamino)-N-(1-(4-cyanobenzyl)piperidin-4- yl)picolinamide

140 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(3,5-difluorobenzyl)piperazine-1- carbonyl)picolinamide

141 5-(4-(4-carbamoylbenzyl)piperidine-1-carbonyl)-N-(1-(4-cyanobenzyl)piperidin-4- yl)picolinamide

142 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4- ((4-fluorophenyl)(hydroxy)methyl)piperidine-1- carbonyl)picolinamide

143 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-methoxyphenoxy)piperidine-1- carbonyl)picolinamide

144 N2-(2-(4-cyanobenzyl)-1,2,3,4- tetrahydroisoquinolin-7-yl)-N5-(4-fluorobenzyl)pyridine-2,5-dicarboxamide

145 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-methylbenzyl)piperidine-1- carbonyl)picolinamide

146 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(3-fluoro-4-methoxybenzyl)piperidine-1- carbonyl)picolinamide

147 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(3-methoxybenzyl)piperidine-1- carbonyl)picolinamide

148 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-fluorophenoxy)piperidine-1- carbonyl)picolinamide

149 N2-(1-(4-cyanobenzyl)piperidin-4-yl)-N5-(2-(4-fluorophenoxy)ethyl)pyridine-2,5- dicarboxamide

150 N-(cis-4-(4-cyanophenoxy)cyclohexyl)-5-(4-(4-fluorobenzyl)piperazine-1- carbonyl)picolinamide

151 N-(trans-4-(4-cyanophenoxy)cyclohexyl)-5-(4-(4-fluorobenzoyl)piperazine-1- carbonyl)picolinamide

152 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(3-(4-fluorobenzyl)piperidine-1- carbonyl)picolinamide

153 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(2-(4-fluorobenzyl)piperidine-1- carbonyl)picolinamide

154 5-(4-(4-chlorobenzoyl)piperidine-1-carbonyl)-N-(1-(4-cyanobenzyl)piperidin-4- yl)picolinamide

155 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(3-cyanophenoxy)piperidine-1- carbonyl)picolinamide

156 5-(4-(3-chloro-4-cyanophenoxy)piperidine-1-carbonyl)-N-(1-(4-cyanobenzyl)piperidin- 4-yl)picolinamide

157 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-(trifluoromethyl)phenoxy)piperidine-1- carbonyl)picolinamide

158 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(3,4-difluorophenoxy)piperidine-1- carbonyl)picolinamide

159 N-(1-(4-cyanobenzyl)piperidin-4-yl)-3-(5,20-dioxo-24-((3aS,4S,6aR)-2- oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-7,10,13,16-tetraoxa-4,19-diazatetracos-1-ynyl)-5-(4-(4-fluorobenzyl)piperazine-1- carbonyl)picolinamide

160 5-(4-(4-fluorobenzoyl)piperidine-1- carbonyl)-N-(1-(4-methoxybenzyl)piperidin-4-yl)picolinamide

161 5-(4-(4-fluorophenoxy)piperidine-1- carbonyl)-N-(1-(4-methoxybenzyl)piperidin-4-yl)picolinamide

162 5-(4-(4-cyanophenoxy)piperidine-1- carbonyl)-N-(1-(4-methoxybenzyl)piperidin-4-yl)picolinamide

163 5-(4-(4-methoxybenzoyl)piperidine-1- carbonyl)-N-(1-(4-methoxybenzyl)piperidin-4-yl)picolinamide

164 tert-butyl 3-(2-(1-(4-cyanobenzyl)piperidin- 4-ylcarbamoyl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)pyridin- 3-yl)prop-2-ynylcarbamate

165 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-cyanophenoxy)piperidin-1- yl)picolinamide

166 N2-(1-(4-cyanobenzyl)piperidin-4-yl)-N5-(1-(4-cyanophenyl)piperidin-4-yl)pyridine- 2,5-dicarboxamide

167 N-((cis)-4-(4-cyanophenoxy)cyclohexyl)-5-(4-(4-fluorophenoxy)piperidine-1- carbonyl)picolinamide

168 N-((trans)-4-(4-cyanophenoxy)cyclohexyl)-5-(4-(4-fluorobenzoyl)piperidine-1- carbonyl)picolinamide

169 N-((trans)-4-(4-cyanophenoxy)cyclohexyl)-5-(4-(4-fluorophenoxy)piperidine-1- carbonyl)picolinamide

170 N-(5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)pyridin-2-yl)biphenyl-4- carboxamide

171 N-((cis)-4-(4-cyanophenoxy)cyclohexyl)-5-(4-(4-methoxybenzoyl)piperidine-1- carbonyl)picolinamide

172 N-((trans)-4-(4-cyanophenoxy)cyclohexyl)-5-(4-(4-methoxyphenoxy)piperidine-1- carbonyl)picolinamide

173 1-(4-cyanobenzyl)-N-(5-(4-(4- fluorophenoxy)piperidine-1-carbonyl)pyridin-2-yl)piperidine-4- carboxamide

174 N-((cis)-4-(4-cyanophenoxy)cyclohexyl)-5-(4-(4-methoxyphenoxy)piperidine-1- carbonyl)picolinamide

175 1-(4-cyanobenzyl)-N-(5-(4-(4- fluorobenzoyl)piperidine-1-carbonyl)pyridin-2-yl)piperidine-4- carboxamide

176 N-((cis)-4-(4-cyanophenoxy)cyclohexyl)-5-((S)-3-(4-fluorophenoxy)pyrrolidine-1- carbonyl)picolinamide

177 N-(5-(4-(4-fluorobenzyl)piperazine-1- carbonyl)pyridin-2-yl)-6-(4-fluorophenoxy)nicotinamide

178 N-(1-(4-fluorobenzyl)piperidin-4-yl)-5-(4-(4-methoxybenzoyl)piperidine-1- carbonyl)picolinamide

179 N-(1-(4-fluorobenzyl)piperidin-4-yl)-5-(4-(4-(trifluoromethyl)phenoxy)piperidine-1- carbonyl)picolinamide

180 N-(1-(4-fluorobenzyl)piperidin-4-yl)-5-(4-(4-fluorophenoxy)piperidine-1- carbonyl)picolinamide

181 5-(4-(4-fluorobenzoyl)piperidine-1-carbonyl)-N-(1-(4-fluorobenzyl)piperidin-4- yl)picolinamide

182 (S)-N-(1-(4-fluorobenzyl)piperidin-4-yl)-5-(3-(4-fluorophenoxy)pyrrolidine-1- carbonyl)picolinamide

183 N-(1-(4-fluorobenzyl)piperidin-4-yl)-5-(4-(4-methoxyphenoxy)piperidine-1- carbonyl)picolinamide

184 5-(4-(4-methoxybenzoyl)piperidine-1- carbonyl)-N-((cis)-4-(4-methoxyphenoxy)cyclohexyl)picolinamide

185 N-((cis)-4-(4-methoxyphenoxy)cyclohexyl)- 5-(4-(4-(trifluoromethyl)phenoxy)piperidine-1- carbonyl)picolinamide

186 N-((cis)-4-(4-methoxyphenoxy)cyclohexyl)-5-(4-(4-methoxyphenoxy)piperidine-1- carbonyl)picolinamide

187 (4-(4-fluorobenzyl)piperazin-1-yl)(6-(4-(4-(trifluoromethyl)phenoxy)piperidin-1- yl)pyridin-3-yl)methanone

188 4-(1-(5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)pyridin-2-yl)piperidin-4- yloxy)benzonitrile

189 (4-(4-fluorobenzyl)piperazin-1-yl)(6-(4-(4-methoxybenzoyl)piperidin-1-yl)pyridin-3- yl)methanone

190 N-((cis)-4-(4-cyanophenoxy)cyclohexyl)-5-(4-(4-(trifluoromethyl)phenoxy)piperidine- 1-carbonyl)picolinamide

191 5-(4-(4-methoxyphenoxy)piperidine-1- carbonyl)-N-((cis)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl) picolinamide

192 5-(4-(4-methoxybenzoyl)piperidine-1- carbonyl)-N-((cis)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl) picolinamide

193 5-(4-(4-cyanophenoxy)piperidine-1- carbonyl)-N-((cis)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl) picolinamide

194 5-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)-N-(1-(4-(pyrrolidin-1- yl)benzyl)piperidin-4-yl)picolinamide

195 5-(4-(4-methoxyphenoxy)piperidine-1-carbonyl)-N-(1-(4-(pyrrolidin-1- yl)benzyl)piperidin-4-yl)picolinamide

196 5-(4-(4-fluorophenoxy)piperidine-1- carbonyl)-N-(1-(4-(pyrrolidin-1-yl)benzyl)piperidin-4-yl)picolinamide

197 5-(4-(4-cyanophenoxy)piperidine-1- carbonyl)-N-(1-(4-(pyrrolidin-1-yl)benzyl)piperidin-4-yl)picolinamide

198 N-((cis)-4-(4-cyano-3- fluorophenoxy)cyclohexyl)-5-(4-(4-methoxybenzoyl)piperidine-1- carbonyl)picolinamide

199 N-((cis)-4-(4-cyano-3- fluorophenoxy)cyclohexyl)-5-(4-(4-(trifluoromethyl)phenoxy)piperidine-1- carbonyl)picolinamide

200 5-(4-(4-cyanophenoxy)piperidine-1-carbonyl)-N-(1-(4-fluorobenzyl)piperidin-4- yl)picolinamide

201 N-(1-(4-carbamoylbenzyl)piperidin-4-yl)-5-(4-(4-fluorobenzyl)piperazine-1- carbonyl)picolinamide

202 N-(1-(4-methoxybenzyl)piperidin-4-yl)-5-(4-(4-(methylsulfonyl)phenoxy)piperidine- 1-carbonyl)picolinamide

203 N-(1-(3,5-difluorobenzyl)piperidin-4-yl)-5-(4-(4-(methylsulfonyl)phenoxy)piperidine- 1-carbonyl)picolinamide

204 N-(6-(4-fluorophenoxy)pyridin-3-yl)-5-(4-(4-methoxybenzoyl)piperidine-1- carbonyl)pyrazine-2-carboxamide

205 N-(6-(4-fluorophenoxy)pyridin-3-yl)-5-(4-(4-(trifluoromethyl)phenoxy)piperidine-1-carbonyl)pyrazine-2-carboxamide

206 5-(4-(2,4-difluorobenzoyl)piperidine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3- yl)pyrazine-2-carboxamide

207 N-(6-(4-fluorophenoxy)pyridin-3-yl)-5-(4-(4-(methylsulfonyl)phenoxy)piperidine-1- carbonyl)pyrazine-2-carboxamide

208 5-(4-(4- (methylsulfonyl)phenoxy)piperidine-1-carbonyl)-N-(1-(4-(pyrrolidin-1- yl)benzyl)piperidin-4-yl)picolinamide

209 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(3-(4-cyanophenoxy)azetidine-1- carbonyl)picolinamide

210 5-(3-(4-cyanophenoxy)azetidine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3- yl)picolinamide

211 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-methoxybenzoyl)piperidine-1- carbonyl)pyrazine-2-carboxamide

212 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-(trifluoromethyl)phenoxy)piperidine-1-carbonyl)pyrazine-2-carboxamide

213 6-(4-(2,4-difluorobenzoyl)piperidine-1- carbonyl)-N-(1-(4-(methylsulfonyl)benzyl)piperidin-4- yl)nicotinamide

214 6-(4-(4-cyanophenoxy)piperidine-1- carbonyl)-N-(1-(4-(methylsulfonyl)benzyl)piperidin-4- yl)nicotinamide

215 6-(4-(4-methoxybenzoyl)piperidine-1- carbonyl)-N-(1-(4-(methylsulfonyl)benzyl)piperidin-4- yl)nicotinamide

216 6-(4-(2,4-difluorobenzoyl)piperidine-1- carbonyl)-N-(1-(4-(methylsulfonamido)benzyl)piperidin-4- yl)nicotinamide

217 6-(4-(4-cyanophenoxy)piperidine-1- carbonyl)-N-(1-(4-(methylsulfonamido)benzyl)piperidin-4- yl)nicotinamide

218 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-(methylsulfonyl)phenoxy)piperidine-1- carbonyl)pyrazine-2-carboxamide

219 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-(pyrrolidin-1-yl)benzoyl)piperidine-1-carbonyl)pyrazine-2-carboxamide

220 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4- (4-(4-methylpiperazin-1-yl)benzoyl)piperidine-1-carbonyl)pyrazine- 2-carboxamide

221 N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(4-(methylsulfonyl)benzoyl)piperidine-1- carbonyl)nicotinamide

222 N-(1-(4-fluorobenzyl)piperidin-4-yl)-6-(4-(4-(methylsulfonyl)benzoyl)piperidine-1- carbonyl)nicotinamide

223 N-(1-(4-methoxybenzyl)piperidin-4-yl)-6-(4-(4-(methylsulfonyl)benzoyl)piperidine-1- carbonyl)nicotinamide

224 N-(6-(4-fluorophenoxy)pyridin-3-yl)-6-(4-(4-(methylsulfonyl)benzoyl)piperidine-1- carbonyl)nicotinamide

225 N-(1-(4-fluorobenzyl)piperidin-4-yl)-5-(4-(4-(methylsulfonyl)benzoyl)piperidine-1- carbonyl)picolinamide

226 N-(1-(4-fluorobenzyl)piperidin-4-yl)-5-(4-(4-(methylsulfonyl)phenoxy)piperidine-1- carbonyl)picolinamide

227 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-(methylsulfonyl)phenoxy)piperidine-1- carbonyl)picolinamide

228 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-(methylsulfonyl)benzoyl)piperidine-1- carbonyl)picolinamide

229 6-(4-(4-(methylsulfonyl)benzoyl)piperidine-1-carbonyl)-N-(1-(4-(pyrrolidin-1- yl)benzyl)piperidin-4-yl)nicotinamide

230 6-(4-(4- (methylsulfonyl)phenoxy)piperidine-1-carbonyl)-N-(1-(4-(pyrrolidin-1- yl)benzyl)piperidin-4-yl)nicotinamide

231 N-(6-(4-fluorophenoxy)pyridin-3-yl)-5-(4-(4-(methylsulfonyl)phenoxy)piperidine-1- carbonyl)picolinamide

232 N-(6-(4-fluorophenoxy)pyridin-3-yl)-5-(4-(4-(methylsulfonyl)benzoyl)piperidine-1- carbonyl)picolinamide

233 5-(4-(4-(methylsulfonyl)benzoyl)piperidine-1-carbonyl)-N-(1-(4-(pyrrolidin-1- yl)benzyl)piperidin-4-yl)picolinamide

234 N-(1-(4-methoxybenzyl)piperidin-4-yl)-5-(4-(4-(methylsulfonyl)benzoyl)piperidine-1- carbonyl)picolinamide

235 N-(6-(4-fluorophenoxy)pyridin-3-yl)-6-(4-(4-(methylsulfonyl)phenoxy)piperidine-1- carbonyl)nicotinamide

236 N-(1-(3,5-difluorobenzyl)piperidin-4-yl)-6-(4-(4-(methylsulfonyl)phenoxy)piperidine- 1-carbonyl)nicotinamide

237 N-(1-(4-methoxybenzyl)piperidin-4-yl)-6-(4-(4-(methylsulfonyl)phenoxy)piperidine- 1-carbonyl)nicotinamide

238 N-(1-(3-methoxybenzyl)piperidin-4-yl)-6-(4-(4-(methylsulfonyl)phenoxy)piperidine- 1-carbonyl)nicotinamide

239 6-(4-(4- (methylsulfonyl)phenoxy)piperidine-1- carbonyl)-N-(1-(3-(trifluoromethoxy)benzyl)piperidin-4- yl)nicotinamide

240 6-(4-(4-azidobenzoyl)piperidine-1-carbonyl)-N-(1-(4-cyanobenzyl)piperidin-4- yl)nicotinamide

241 N-(1-(3-methoxybenzyl)piperidin-4-yl)-5-(4-(4-(methylsulfonyl)phenoxy)piperidine- 1-carbonyl)picolinamide

242 5-(4-(4- (methylsulfonyl)phenoxy)piperidine-1- carbonyl)-N-(1-(3-(trifluoromethoxy)benzyl)piperidin-4- yl)picolinamide

243 N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4- (4-(4-methylpiperazin-1-yl)benzoyl)piperidine-1- carbonyl)nicotinamide

244 6-(4-(4-(4-methylpiperazin-1-yl)benzoyl)piperidine-1-carbonyl)-N-(1-(4-(trifluoromethoxy)benzyl)piperidin-4- yl)nicotinamide

245 N-(6-(4-fluorophenoxy)pyridin-3-yl)-6-(4- (4-(4-methylpiperazin-1-yl)benzoyl)piperidine-1- carbonyl)nicotinamide

246 N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4- (4-(cyclopropylsulfonyl)phenoxy)piperidine-1- carbonyl)nicotinamide

247 6-(4-(4- (cyclopropylsulfonyl)phenoxy)piperidine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3- yl)nicotinamide

248 6-(4-(4- (cyclopropylsulfonyl)phenoxy)piperidine-1-carbonyl)-N-(1-(4-(pyrrolidin-1- yl)benzyl)piperidin-4-yl)nicotinamide

249 6-(4-(4- (cyclopropylsulfonyl)phenoxy)piperidine-1-carbonyl)-N-(1-(4- (trifluoromethoxy)benzyl)piperidin-4- yl)nicotinamide

250 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)picolinamide

251 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-(isopropylsulfonyl)phenyl)piperazine-1- carbonyl)picolinamide

252 N-((trans)-1-(4-cyanobenzyl)-3- fluoropiperidin-4-yl)-5-(4-(4-(methylsulfonyl)benzoyl)piperidine-1- carbonyl)picolinamide

253 N-((trans)-3-fluoro-1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-5-(4-(4-(methylsulfonyl)benzoyl)piperidine-1- carbonyl)picolinamide

254 N-((trans)-1-(4-cyanobenzyl)-3- fluoropiperidin-4-yl)-5-(4-(4-(methylsulfonyl)phenoxy)piperidine-1- carbonyl)picolinamide

255 N-((trans)-3-fluoro-1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-5-(4-(4-(methylsulfonyl)phenoxy)piperidine- 1-carbonyl)picolinamide

256 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-(cyclopropylsulfonyl)phenyl)piperazine- 1-carbonyl)picolinamide

257 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4- (4-(trifluoromethylsulfonyl)phenyl)piperazine- 1-carbonyl)picolinamide

258 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4- (4-(cyclopropanecarbonyl)phenyl)piperazine- 1-carbonyl)picolinamide

259 N-(6-(4-acetylphenoxy)pyridin-3-yl)-5-(4-(4-(methylsulfonyl)phenoxy)piperidine-1- carbonyl)picolinamide

260 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-(ethylsulfonyl)benzoyl)piperidine-1- carbonyl)picolinamide

261 N-(6-(4-fluorophenylsulfonyl)pyridin-3-yl)- 5-(4-(4-(methylsulfonyl)phenoxy)piperidine-1- carbonyl)picolinamide

262 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-fluorophenylsulfonyl)piperidine-1- carbonyl)picolinamide

263 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-(2,2,2-trifluoroacetyl)phenyl)piperazine- 1-carbonyl)picolinamide

264 N2,N5-bis(1-benzylpiperidin-4-yl)pyridine- 2,5-dicarboxamide

265 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(3-(4-cyanophenoxy)piperidin-1- yl)picolinamide

266 5-(4-(4-chlorobenzoyl)piperidin-1-yl)-N-(1-(4-cyanobenzyl)piperidin-4-yl)picolinamide

267 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(1-(4-cyanophenyl)piperidin-4- ylamino)picolinamide

268 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(2-(4-fluorophenyl)propan-2-yl)piperazine- 1-carbonyl)picolinamide

269 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(pyridin-4-yloxy)piperidine-1- carbonyl)picolinamide

270 (S)-N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(3-(4-fluorophenoxy)pyrrolidine-1- carbonyl)picolinamide

271 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(2,4-difluorobenzoyl)piperidine-1- carbonyl)picolinamide

272 5-(4-(4-fluorobenzoyl)piperidine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3- yl)picolinamide

273 5-(4-(4-fluorophenoxy)piperidine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3- yl)picolinamide

274 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(3-(4-methoxyphenoxy)piperidine-1- carbonyl)picolinamide

275 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(1-(4-methoxyphenyl)piperidin-4- ylamino)picolinamide

276 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(1-(4-fluorophenyl)piperidin-4- ylamino)picolinamide

277 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(3-(3-methoxyphenoxy)piperidine-1- carbonyl)picolinamide

278 (R)-N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(3-(4-fluorophenoxy)pyrrolidine-1- carbonyl)picolinamide

279 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-((trans)-4-(4-cyanophenoxy)-3- fluoropiperidine-1-carbonyl)picolinamide

280 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-((1R,3r,5S)-3-(4-cyanophenoxy)-8- azabicyclo[3.2.1]octane-8-carbonyl)picolinamide

281 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(3,4-difluorobenzoyl)piperidine-1- carbonyl)picolinamide

282 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(2,4-difluorophenoxy)piperidine-1- carbonyl)picolinamide

283 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(pyridin-3-yloxy)piperidine-1- carbonyl)picolinamide

284 ethyl 4-(1-(6-(1-(4-cyanobenzyl)piperidin-4-ylcarbamoyl)nicotinoyl)piperidin-4- yloxy)benzoate

285 5-(4-(4-cyanobenzyl)piperazine-1- carbonyl)-N-(1-(4-methoxybenzyl)piperidin-4-yl)picolinamide

286 5-(4-(4-cyano-2- methoxyphenoxy)piperidin-1-yl)-N-(1-(4-cyanobenzyl)piperidin-4-yl)picolinamide

287 N-(1-(3,5-difluorobenzyl)piperidin-4-yl)-5-(4-(4-methoxybenzoyl)piperidine-1- carbonyl)picolinamide

288 N-(1-(3,5-difluorobenzyl)piperidin-4-yl)-5-(4-(4-fluorobenzoyl)piperidine-1- carbonyl)picolinamide

289 5-(4-(4-cyanophenoxy)piperidine-1- carbonyl)-N-(1-(3,5-difluorobenzyl)piperidin-4-yl)picolinamide

290 tert-butyl 3-(2-(1-(4-cyanobenzyl)piperidin- 4-ylcarbamoyl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)pyridin- 3-yl)propylcarbamate

291 N-(1-(4-cyanobenzyl)piperidin-4-yl)-3-(5,21-dioxo-25-((3aS,4S,6aR)-2- oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-8,11,14,17-tetraoxa-4,20- diazapentacosyl)-5-(4-(4-fluorobenzyl)piperazine-1- carbonyl)picolinamide

292 N-(1-(3,5-difluorobenzyl)piperidin-4-yl)-5-((S)-3-(4-fluorophenoxy)pyrrolidine-1- carbonyl)picolinamide

293 N-(1-(3,5-difluorobenzyl)piperidin-4-yl)-5-(4-(p-tolyloxy)piperidine-1- carbonyl)picolinamide

294 N-(1-(3,5-difluorobenzyl)piperidin-4-yl)-5-(4-(4-(trifluoromethyl)phenoxy)piperidine- 1-carbonyl)picolinamide

295 N-(1-(3,5-difluorobenzyl)piperidin-4-yl)-5-(4-(4-fluorophenoxy)piperidine-1- carbonyl)picolinamide

296 N-(1-(3,5-difluorobenzyl)piperidin-4-yl)-5-(4-(4-methoxyphenoxy)piperidine-1- carbonyl)picolinamide

297 N-(1-(3,5-difluorobenzyl)piperidin-4-yl)-5-(4-(3,4-difluorophenoxy)piperidine-1- carbonyl)picolinamide

298 5-(4-(3,4-difluorobenzoyl)piperidine-1- carbonyl)-N-(1-(3,5-difluorobenzyl)piperidin-4-yl)picolinamide

299 N-((cis)-4-(3,5- difluorophenoxy)cyclohexyl)-5-(4-(4-fluorophenoxy)piperidine-1- carbonyl)picolinamide

300 N-((cis)-4-(3,5- difluorophenoxy)cyclohexyl)-5-(4-(4-methoxybenzoyl)piperidine-1- carbonyl)picolinamide

301 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-(trifluoromethyl)phenoxy)piperidin-1- yl)picolinamide

302 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-methoxybenzoyl)piperidin-1- yl)picolinamide

303 5-(4-(4-cyanophenoxy)piperidine-1- carbonyl)-N-((cis)-4-(4-fluorophenoxy)cyclohexyl)picolinamide

304 5-(4-(4-fluorobenzoyl)piperidine-1- carbonyl)-N-((cis)-4-(4-fluorophenoxy)cyclohexyl)picolinamide

305 N-(2-(4-fluorophenoxy)ethyl)-5-(4-(4- methoxybenzoyl)piperidine-1-carbonyl)picolinamide

306 5-(4-(4-cyanophenoxy)piperidine-1- carbonyl)-N-(2-(4-fluorophenoxy)ethyl)picolinamide

307 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(3-(4-fluorobenzyloxy)azetidine-1- carbonyl)picolinamide

308 N-(1-(3,5-difluorobenzyl)piperidin-4-yl)-5-(3-(4-fluorobenzyloxy)azetidine-1- carbonyl)picolinamide

309 N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1- carbonyl)nicotinamide

310 N-(1-(3,5-difluorobenzyl)piperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1- carbonyl)nicotinamide

311 N-((cis)-4-(4-fluorophenoxy)cyclohexyl)-5-(4-(4-methoxybenzoyl)piperidine-1- carbonyl)picolinamide

312 N-((cis)-4-(4-fluorophenoxy)cyclohexyl)-5-(4-(4-fluorophenoxy)piperidine-1- carbonyl)picolinamide

313 5-(3-(4-cyanophenoxy)azetidine-1- carbonyl)-N-(1-(3,5-difluorobenzyl)piperidin-4-yl)picolinamide

314 5-(3-(4-cyanophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl)-N-(1-(3,5-difluorobenzyl)piperidin-4- yl)picolinamide

315 N-((1s,4s)-4-(4-cyanophenoxy)cyclohexyl)-6-(4-(4-methoxybenzoyl)piperidine-1- carbonyl)nicotinamide

316 N-((cis)-4-(4-fluorophenoxy)cyclohexyl)-6-(4-(4-methoxybenzoyl)piperidine-1- carbonyl)nicotinamide

317 N-(1-(4-fluorobenzyl)piperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1- carbonyl)nicotinamide

318 6-(4-(4-methoxybenzoyl)piperidine-1- carbonyl)-N-(1-(4-methoxybenzyl)piperidin-4-yl)nicotinamide

319 6-(4-(4-cyanophenoxy)piperidine-1- carbonyl)-N-(1-(4-methoxybenzyl)piperidin-4-yl)nicotinamide

320 6-(4-(4-cyanophenoxy)piperidine-1-carbonyl)-N-(1-(4-fluorobenzyl)piperidin-4- yl)nicotinamide

321 N-((cis)-4-(4-cyanophenoxy)cyclohexyl)-6-(4-(4-cyanophenoxy)piperidine-1- carbonyl)nicotinamide

322 6-(4-(4-cyanophenoxy)piperidine-1- carbonyl)-N-(1-(3,5-difluorobenzyl)piperidin-4-yl)nicotinamide

323 N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(4-cyanophenoxy)piperidine-1- carbonyl)nicotinamide

324 6-(4-(4-cyanophenoxy)piperidine-1- carbonyl)-N-((cis)-4-(4-fluorophenoxy)cyclohexyl)nicotinamide

325 N-(6-(4-fluorophenoxy)pyridin-3-yl)-6-(4-(4-methoxybenzoyl)piperidine-1- carbonyl)nicotinamide

326 6-(4-(4-cyanophenoxy)piperidine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3- yl)nicotinamide

327 6-(4-(4-fluorobenzyl)piperazine-1- carbonyl)-N-(1-(4-methoxybenzyl)piperidin-4-yl)nicotinamide

328 6-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(1-(4-fluorobenzyl)piperidin-4- yl)nicotinamide

329 5-(4-(3,4-difluorobenzoyl)piperidine-1- carbonyl)-N-(1-(4-methoxybenzyl)piperidin-4-yl)picolinamide

330 5-(4-(3,4-difluorobenzoyl)piperidine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3- yl)picolinamide

331 5-(4-(2,4-difluorobenzoyl)piperidine-1- carbonyl)-N-(1-(4-methoxybenzyl)piperidin-4-yl)picolinamide

332 N-((cis)-4-(4-cyanophenoxy)cyclohexyl)-6-(4-(4-fluorobenzyl)piperazine-1- carbonyl)nicotinamide

333 tert-butyl 4-(6-(4-(4- cyanophenoxy)piperidine-1-carbonyl)nicotinamido)piperidine-1- carboxylate

334 6-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3- yl)nicotinamide

335 6-(4-(4-cyanophenoxy)piperidine-1-carbonyl)-N-(piperidin-4-yl)nicotinamide

336 6-(4-(4-cyanophenoxy)piperidine-1- carbonyl)-N-(1-(4-(pyrrolidin-1-yl)benzyl)piperidin-4-yl)nicotinamide

337 6-(4-(4-cyanophenoxy)piperidine-1- carbonyl)-N-(1-(4-morpholinobenzyl)piperidin-4- yl)nicotinamide

338 6-(4-(4-cyanophenoxy)piperidine-1- carbonyl)-N-(1-(4-(trifluoromethoxy)benzyl)piperidin-4- yl)nicotinamide

339 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-(trifluoromethyl)phenyl)piperazine-1- carbonyl)picolinamide

340 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-cyanophenyl)piperazine-1- carbonyl)picolinamide

341 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-fluorophenyl)piperazine-1- carbonyl)picolinamide

342 5-(4-(2,4-difluorobenzoyl)piperidine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3- yl)picolinamide

343 6-(4-(2,4-difluorophenoxy)piperidine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3- yl)nicotinamide

344 6-(4-(2,4-difluorophenoxy)piperidine-1- carbonyl)-N-(1-(4-methoxybenzyl)piperidin-4-yl)nicotinamide

345 N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(2,4-difluorophenoxy)piperidine-1- carbonyl)nicotinamide

346 N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(2,4-difluorobenzoyl)piperidine-1- carbonyl)nicotinamide

347 6-(4-(2,4-difluorobenzoyl)piperidine-1- carbonyl)-N-(1-(4-methoxybenzyl)piperidin-4-yl)nicotinamide

348 6-(4-(2,4-difluorobenzoyl)piperidine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3- yl)nicotinamide

349 N-((trans)-1-(4-cyanobenzyl)-3- fluoropiperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1- carbonyl)nicotinamide

350 N-((trans)-3-fluoro-1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1- carbonyl)nicotinamide

351 N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(4-cyanophenoxy)piperidin-1-yl)pyridazine- 3-carboxamide

352 N-((trans)-3-fluoro-1-(4-(pyrrolidin-1-yl)benzyl)piperidin-4-yl)-6-(4-(4- methoxybenzoyl)piperidine-1-carbonyl)nicotinamide

353 N-((trans)-3-fluoro-1-(4- isopropoxybenzyl)piperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1- carbonyl)nicotinamide

354 N-((trans)-1-(4-cyano-3-fluorobenzyl)-3-fluoropiperidin-4-yl)-6-(4-(4- methoxybenzoyl)piperidine-1-carbonyl)nicotinamide

355 6-(4-(4-cyanophenoxy)piperidine-1- carbonyl)-N-(1-(oxazol-4-ylmethyl)piperidin-4-yl)nicotinamide

356 6-(4-(4-cyanophenoxy)piperidine-1- carbonyl)-N-(1-(thiazol-2-ylmethyl)piperidin-4-yl)nicotinamide

357 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-(dimethylcarbamoyl)phenoxy)piperidine- 1-carbonyl)picolinamide

358 5-(4-(4-acetylphenoxy)piperidine-1-carbonyl)-N-(1-(4-cyanobenzyl)piperidin-4- yl)picolinamide

359 5-(4-(4-acetylphenoxy)piperidine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3- yl)picolinamide

360 5-(4-(4- (dimethylcarbamoyl)phenoxy)piperidine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3- yl)picolinamide

361 N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(4-(trifluoromethyl)phenoxy)piperidin-1- yl)pyridazine-3-carboxamide

362 N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidin-1- yl)pyridazine-3-carboxamide

363 N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(4-nitrophenoxy)piperidine-1- carbonyl)nicotinamide

364 6-(4-(4-aminophenoxy)piperidine-1-carbonyl)-N-(1-(4-cyanobenzyl)piperidin-4- yl)nicotinamide

365 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-(pyrrolidin-1-yl)benzoyl)piperidine-1- carbonyl)picolinamide

366 6-(4-(4-acetamidophenoxy)piperidine-1-carbonyl)-N-(1-(4-cyanobenzyl)piperidin-4- yl)nicotinamide

367 N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(4-(methylsulfonamido)phenoxy)piperidine- 1-carbonyl)nicotinamide

368 N-(6-(4-fluorophenoxy)pyridin-3-yl)-5-(4-(4-(pyrrolidin-1-yl)benzoyl)piperidine-1- carbonyl)picolinamide

369 5-(4-(4-cyanobenzoyl)piperidine-1-carbonyl)-N-(1-(4-cyanobenzyl)piperidin-4- yl)picolinamide

370 N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(4-(dimethylamino)phenoxy)piperidine-1- carbonyl)nicotinamide

371 N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(4-(17-oxo-20-((3aS,4S,6aR)-2- oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-4,7,10,13-tetraoxa-16- azaicosanamido)phenoxy)piperidine-1-carbonyl)nicotinamide

372 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-(methylthio)benzoyl)piperidine-1- carbonyl)picolinamide

373 6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)-N-(1-(4-nitrobenzyl)piperidin-4- yl)nicotinamide

374 1-(4-cyanobenzyl)-4-(5-(4-(4- (methylsulfinyl)benzoyl)piperidine-1-carbonyl)picolinamido)piperidine 1-oxide

375 5-(4-(4-(1H-pyrazol-1- yl)benzoyl)piperidine-1-carbonyl)-N-(1-(4-cyanobenzyl)piperidin-4-yl)picolinamide

376 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-morpholinobenzoyl)piperidine-1- carbonyl)picolinamide

377 N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(4-(pyrrolidin-1-yl)benzoyl)piperidine-1- carbonyl)nicotinamide

378 N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(4-methoxy-2-nitrophenoxy)piperidine-1- carbonyl)nicotinamide

379 N-(6-(4-fluorophenoxy)pyridin-3-yl)-5-(4-(4-morpholinobenzoyl)piperidine-1- carbonyl)picolinamide

380 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4- (4-(4-methylpiperazin-1-yl)benzoyl)piperidine-1- carbonyl)picolinamide

381 N-(1-(4-fluorobenzyl)piperidin-4-yl)-6-(4-(4-(pyrrolidin-1-yl)benzoyl)piperidine-1- carbonyl)nicotinamide

382 N-(6-(4-fluorophenoxy)pyridin-3-yl)-6-(4-(4-(pyrrolidin-1-yl)benzoyl)piperidine-1- carbonyl)nicotinamide

383 6-(4-(2-acetamido-4- methoxyphenoxy)piperidine-1-carbonyl)-N-(1-(4-cyanobenzyl)piperidin-4- yl)nicotinamide

384 6-(4-(2-amino-4- methoxyphenoxy)piperidine-1-carbonyl)-N-(1-(4-cyanobenzyl)piperidin-4- yl)nicotinamide

385 N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4- (2-(dimethylamino)-4-methoxyphenoxy)piperidine-1- carbonyl)nicotinamide

386 N3,N6-bis(1-(4-cyanobenzyl)piperidin-4-yl)pyridazine-3,6-dicarboxamide

387 N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1- carbonyl)pyridazine-3-carboxamide

388 N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(4-cyanophenoxy)piperidine-1- carbonyl)pyridazine-3-carboxamide

389 N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4- (4-methoxy-2-(methylsulfonamido)phenoxy)piperidine-1- carbonyl)nicotinamide

390 6-(4-(4-acetylphenoxy)piperidine-1-carbonyl)-N-(1-(4-cyanobenzyl)piperidin-4- yl)nicotinamide

391 6-(4-(4-acetylphenoxy)piperidine-1-carbonyl)-N-(1-(4-fluorobenzyl)piperidin-4- yl)nicotinamide

392 6-(4-(4-(1H-pyrazol-1- yl)benzoyl)piperidine-1-carbonyl)-N-(1-(4-fluorobenzyl)piperidin-4-yl)nicotinamide

393 6-(4-(4-(1H-pyrazol-1- yl)benzoyl)piperidine-1-carbonyl)-N-(1-(4-cyanobenzyl)piperidin-4-yl)nicotinamide

394 N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(4-methoxy-2-(17-oxo-21-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4- yl)-4,7,10,13-tetraoxa-16-azahenicosanamido)phenoxy)piperidine-1- carbonyl)nicotinamide

395 6-(4-(4-acetylphenoxy)piperidine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3- yl)nicotinamide

396 N-(1-(4-fluorobenzyl)piperidin-4-yl)-6-(4-(4-(methylsulfonyl)phenoxy)piperidine-1- carbonyl)nicotinamide

397 N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(4-(methylsulfonyl)phenoxy)piperidine-1- carbonyl)nicotinamide

398 N-(4-(4-cyanophenoxy)cyclohexyl)-6-(4-(4-(methylsulfonyl)phenoxy)piperidine-1- carbonyl)nicotinamide

399 N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(4-(methylsulfonyl)phenoxy)piperidine-1-carbonyl)pyridazine-3-carboxamide

400 N-(1-(4-aminobenzyl)piperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1- carbonyl)nicotinamide

401 N-(1-(4-acetamidobenzyl)piperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1- carbonyl)nicotinamide

402 6-(4-(4-acetylphenoxy)piperidine-1- carbonyl)-N-(4-(4-cyanophenoxy)cyclohexyl)nicotinamide

403 5-(4-(4-methoxybenzoyl)piperidine-1- carbonyl)-N-(1-(4-(14-oxo-18-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-4,7,10-trioxa-13-azaoctadecanamido)benzyl)piperidin-4- yl)picolinamide

404 6-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(1-(4-fluorophenyl)piperidin-4- yl)nicotinamide

405 6-(4-(4-fluorobenzyl)piperazine-1- carbonyl)-N-(1-(4-methoxyphenyl)piperidin-4-yl)nicotinamide

406 6-(4-(4-acetamidophenoxy)piperidine-1-carbonyl)-N-(1-(4-fluorobenzyl)piperidin-4- yl)nicotinamide

407 6-(4-(4-acetamidophenoxy)piperidine-1- carbonyl)-N-(1-(4-methoxybenzyl)piperidin-4-yl)nicotinamide

408 5-(4-(4-acetamidophenoxy)piperidine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3- yl)picolinamide

409 N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4- (4-(cyclopropanecarboxamido)phenoxy)piperidine- 1-carbonyl)nicotinamide

410 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-(trifluoromethylthio)phenoxy)piperidine- 1-carbonyl)picolinamide

411 6-(4-(3-acetamidophenoxy)piperidine-1-carbonyl)-N-(1-(4-cyanobenzyl)piperidin-4- yl)nicotinamide

412 6-(4-(3-acetamidophenoxy)piperidine-1- carbonyl)-N-(1-(4-methoxybenzyl)piperidin-4-yl)nicotinamide

413 6-(4-(3-acetamidophenoxy)piperidine-1-carbonyl)-N-(1-(4-fluorobenzyl)piperidin-4- yl)nicotinamide

414 6-(4-(3-acetamidophenoxy)piperidine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3- yl)nicotinamide

415 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4- (4-(trifluoromethylsulfonyl)phenoxy)piperidine- 1-carbonyl)picolinamide

416 tert-butyl 3-(5-(1-(4-cyanobenzyl)piperidin- 4-ylcarbamoyl)-2-(4-(4-methoxybenzoyl)piperidine-1- carbonyl)pyridin-3-yl)propylcarbamate

417 N-(1-(4-cyanophenyl)piperidin-4-yl)-6-(4-(4-fluorobenzyl)piperazine-1- carbonyl)nicotinamide

418 6-(4-(4-cyanophenoxy)piperidine-1-carbonyl)-N-(1-(4-cyanophenyl)piperidin-4- yl)nicotinamide

419 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(thiophene-2-carbonyl)piperidine-1- carbonyl)picolinamide

420 6-(4-(4-cyanophenoxy)piperidine-1- carbonyl)-N-(1-(4-(methylsulfonyl)phenyl)piperidin-4- yl)nicotinamide

421 6-(4-(4-fluorobenzyl)piperazine-1- carbonyl)-N-(1-(4-(methylsulfonyl)phenyl)piperidin-4- yl)nicotinamide

422 6-(4-(4-cyanophenoxy)piperidine-1-carbonyl)-N-(1-(4-fluorophenyl)piperidin-4- yl)nicotinamide

423 6-(4-(4-cyanophenoxy)piperidine-1- carbonyl)-N-(1-(4-methoxyphenyl)piperidin-4-yl)nicotinamide

424 6-(4-(4-methoxybenzoyl)piperidine-1- carbonyl)-N-(1-(3-(trifluoromethoxy)benzyl)piperidin-4- yl)nicotinamide

425 6-(4-(4-methoxybenzoyl)piperidine-1- carbonyl)-N-(1-(3-methoxybenzyl)piperidin-4-yl)nicotinamide

426 N-((3S,4R)-3-fluoro-1-((5-methylisoxazol-3-yl)methyl)piperidin-4-yl)-6-(4-(4- methoxybenzoyl)piperidine-1-carbonyl)nicotinamide

427 N-((3S,4R)-3-fluoro-1-((2-methylthiazol-4-yl)methyl)piperidin-4-yl)-6-(4-(4- methoxybenzoyl)piperidine-1-carbonyl)nicotinamide

428 6-(4-(4-acetamidophenoxy)piperidine-1- carbonyl)-N-(1-(3-(trifluoromethoxy)benzyl)piperidin-4- yl)nicotinamide

429 6-(4-(3-acetamidophenoxy)piperidine-1- carbonyl)-N-(1-(3-(trifluoromethoxy)benzyl)piperidin-4- yl)nicotinamide

430 6-(4-(4-methoxybenzoyl)piperidine-1- carbonyl)-N-(1-(4-(trifluoromethoxy)benzyl)piperidin-4- yl)nicotinamide

431 N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4- (3-(cyclopropanecarboxamido)phenoxy)piperidine-1- carbonyl)nicotinamide

432 6-(4-(3- (cyclopropanecarboxamido)phenoxy)piperidine-1-carbonyl)-N-(1-(4- fluorobenzyl)piperidin-4-yl)nicotinamide

433 6-(4-(3- (cyclopropanecarboxamido)phenoxy)piperidine-1-carbonyl)-N-(6-(4- fluorophenoxy)pyridin-3-yl)nicotinamide

434 N-((cis)-4-(4-cyanophenoxy)cyclohexyl)-6- (4-(3-(cyclopropanecarboxamido)phenoxy)piperidine-1- carbonyl)nicotinamide

435 6-(4-(3- (cyclopropanecarboxamido)phenoxy)piperidine-1-carbonyl)-N-(1-(4- methoxybenzyl)piperidin-4-yl)nicotinamide

436 N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(4-(trifluoromethylthio)phenoxy)piperidine-1-carbonyl)pyridazine-3-carboxamide

437 6-(4-(4-acetylphenoxy)piperidine-1-carbonyl)-N-(1-(4-cyanobenzyl)piperidin-4- yl)pyridazine-3-carboxamide

438 6-(4-(3- (cyclopropanecarboxamido)phenoxy)piperidine-1-carbonyl)-N-(1-(4- (trifluoromethoxy)benzyl)piperidin-4- yl)nicotinamide

439 N-(1-(4-methoxybenzyl)piperidin-4-yl)-6-(4-(4-(pyrrolidin-1-yl)benzoyl)piperidine-1- carbonyl)nicotinamide

440 6-(4-(4-(pyrrolidin-1-yl)benzoyl)piperidine- 1-carbonyl)-N-(1-(4-(trifluoromethoxy)benzyl)piperidin-4- yl)nicotinamide

441 6-(4-(4-(pyrrolidin-1-yl)benzoyl)piperidine- 1-carbonyl)-N-(1-(3-(trifluoromethoxy)benzyl)piperidin-4- yl)nicotinamide

442 N-((cis)-4-(4-cyanophenoxy)cyclohexyl)-6-(4-(4-(pyrrolidin-1-yl)benzoyl)piperidine-1- carbonyl)nicotinamide

443 N-(1-(3-fluoro-4-methoxybenzyl)piperidin-4-yl)-6-(4-(4-(pyrrolidin-1- yl)benzoyl)piperidine-1-carbonyl)nicotinamide

444 6-(4-(4-(pyrrolidin-1-yl)benzoyl)piperidine-1-carbonyl)-N-(1-(4-(pyrrolidin-1- yl)benzyl)piperidin-4-yl)nicotinamide

445 6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)-N-(piperidin-4-yl)nicotinamide

446 N-(1-(4-isopropoxybenzyl)piperidin-4-yl)-6-(4-(4-(pyrrolidin-1-yl)benzoyl)piperidine- 1-carbonyl)nicotinamide

447 N-(1-(4-cyano-3-fluorobenzyl)piperidin-4- yl)-6-(4-(4-(pyrrolidin-1-yl)benzoyl)piperidine-1- carbonyl)nicotinamide

448 N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4- (4-(cyclopropanesulfonamido)phenoxy)piperidine-1- carbonyl)nicotinamide

449 6-(4-(4- (cyclopropanesulfonamido)phenoxy)piperidine-1-carbonyl)-N-(6-(4- fluorophenoxy)pyridin-3-yl)nicotinamide

450 N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4- (4-(trifluoromethylsulfonyl)phenoxy)piperidine-1- carbonyl)nicotinamide

451 N-((trans)-1-(4-cyanobenzyl)-3- fluoropiperidin-4-yl)-6-(4-(4-(trifluoromethylsulfonyl)phenoxy)piperidine-1- carbonyl)nicotinamide

452 N-((3R,4R)-1-(4-cyanobenzyl)-3- fluoropiperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1- carbonyl)nicotinamide

453 N-((3S,4S)-1-(4-cyanobenzyl)-3- fluoropiperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1- carbonyl)nicotinamide

454 N-((cis)-1-(4-cyanobenzyl)-3- fluoropiperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1- carbonyl)nicotinamide

455 6-(4-(4- (cyclopropanecarbonyl)phenoxy)piperidine-1-carbonyl)-N-(1-(4- (trifluoromethoxy)benzyl)piperidin-4-yl)nicotinamide

456 N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4- (4-(cyclopropanecarbonyl)phenoxy)piperidine- 1-carbonyl)nicotinamide

457 6-(4-(4- (cyclopropanecarbonyl)phenoxy)piperidine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin- 3-yl)nicotinamide

458 6-(4-(4- (cyclopropanecarbonyl)phenoxy)piperidine-1-carbonyl)-N-(1-(4- methoxybenzyl)piperidin-4-yl)nicotinamide

459 N-(6-(4-cyanophenoxy)pyridin-3-yl)-6-(4-(4-(methylsulfonyl)phenoxy)piperidine-1- carbonyl)nicotinamide

460 N-(6-(4-cyanophenoxy)pyridin-3-yl)-6-(4-(4-methoxybenzoyl)piperidine-1- carbonyl)nicotinamide

461 N-((cis)-3-fluoro-1-(4- (trifluoromethoxy)benzyl)piperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1- carbonyl)nicotinamide

462 N-(6-(4-acetylphenoxy)pyridin-3-yl)-6-(4-(4-methoxybenzoyl)piperidine-1- carbonyl)nicotinamide

463 N-(6-(4-cyanophenoxy)pyridin-3-yl)-6-(4-(2,4-difluorobenzoyl)piperidine-1- carbonyl)nicotinamide

464 N-(6-(4-acetylphenoxy)pyridin-3-yl)-6-(4-(2,4-difluorobenzoyl)piperidine-1- carbonyl)nicotinamide

465 6-(4-(4-methoxybenzoyl)piperidine-1- carbonyl)-N-(6-(4-(methylsulfonyl)phenoxy)pyridin-3- yl)nicotinamide

466 6-(4-(2,4-difluorobenzoyl)piperidine-1- carbonyl)-N-(6-(4-(methylsulfonyl)phenoxy)pyridin-3- yl)nicotinamide

467 N-(6-(4-fluorophenylsulfonyl)pyridin-3-yl)-6-(4-(4-methoxybenzoyl)piperidine-1- carbonyl)nicotinamide

468 N-(5-(4-cyanophenoxy)pyridin-2-yl)-6-(4-(4-methoxybenzoyl)piperidine-1- carbonyl)nicotinamide

469 N-(5-(4-cyanophenoxy)pyridin-2-yl)-6-(4-(2,4-difluorobenzoyl)piperidine-1- carbonyl)nicotinamide

470 6-(4-(4-fluorophenylsulfonyl)piperidine-1- carbonyl)-N-(1-(4-(trifluoromethoxy)benzyl)piperidin-4- yl)nicotinamide

471 N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(4-fluorophenylsulfonyl)piperidine-1- carbonyl)nicotinamide

472 N-(6-(4-cyanophenoxy)pyridin-3-yl)-6-(4-(4-fluorophenylsulfonyl)piperidine-1- carbonyl)nicotinamide

473 N-(6-(4-acetylphenoxy)pyridin-3-yl)-6-(4-(4-fluorophenylsulfonyl)piperidine-1- carbonyl)nicotinamide

474 6-(4-(4-fluorophenylsulfonyl)piperidine-1- carbonyl)-N-(1-(4-methoxybenzyl)piperidin-4-yl)nicotinamide

475 6-(4-(4-fluorophenylsulfonyl)piperidine-1- carbonyl)-N-(1-(3-methoxybenzyl)piperidin-4-yl)nicotinamide

476 N-(6-(4-cyanophenoxy)pyridin-3-yl)-6-(4-(4-fluorobenzyl)piperazine-1- carbonyl)nicotinamide

477 N-(6-(4-acetylphenoxy)pyridin-3-yl)-6-(4-(4-fluorobenzyl)piperazine-1- carbonyl)nicotinamide

478 N-(6-(4-cyanophenoxy)-2-methylpyridin-3-yl)-6-(4-(4-methoxybenzoyl)piperidine-1- carbonyl)nicotinamide

479 N-(6-(4-cyanophenoxy)-2-methylpyridin-3-yl)-6-(4-(2,4-difluorobenzoyl)piperidine-1- carbonyl)nicotinamide

480 N-(6-(4- (dimethylcarbamoyl)phenoxy)pyridin-3-yl)-6-(4-(4-methoxybenzoyl)piperidine-1- carbonyl)nicotinamide

481 6-(4-(2,4-difluorobenzoyl)piperidine-1- carbonyl)-N-(6-(4-(dimethylcarbamoyl)phenoxy)pyridin-3- yl)nicotinamide

482 N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)- N-methylnicotinamide

483 6-(4-(4-methoxybenzoyl)piperidine-1- carbonyl)-N-methyl-N-(1-(4-(trifluoromethoxy)benzyl)piperidin-4- yl)nicotinamide

484 6-(4-(4-methoxybenzoyl)piperidine-1- carbonyl)-N-(1-(4-methoxybenzyl)piperidin-4-yl)-N- methylnicotinamide

485 N-(6-(4-acetylphenoxy)pyridin-3-yl)-6-(4-(4-(methylsulfonyl)phenoxy)piperidine-1- carbonyl)nicotinamide

486 N-(6-(4-acetylphenoxy)pyridin-3-yl)-6-(4- (4-(cyclopropylsulfonyl)phenoxy)piperidine-1- carbonyl)nicotinamide

487 N-(6-(4-acetylphenoxy)pyridin-3-yl)-6-(4-(4-(methylsulfonyl)phenyl)piperazine-1- carbonyl)nicotinamide

488 N-(6-(4-acetylphenoxy)pyridin-3-yl)-6-(4-(4-(dimethylcarbamoyl)phenoxy)piperidine- 1-carbonyl)nicotinamide

489 N-(6-(4-acetylphenoxy)pyridin-3-yl)-6-(4-(4-(isopropylsulfonyl)phenyl)piperazine-1- carbonyl)nicotinamide

490 N-(1-(4- (dimethylcarbamoyl)benzyl)piperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1- carbonyl)nicotinamide

491 N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(4-fluorobenzyl)piperazin-1-yl)pyridazine- 3-carboxamide

492 N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-(pentafluorosulfanyl)phenoxy)piperidine- 1-carbonyl)picolinamide

493 N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(4-(pentafluorosulfanyl)phenoxy)piperidine- 1-carbonyl)nicotinamide

494 6-(4-(4- (pentafluorosulfanyl)phenoxy)piperidine-1-carbonyl)-N-(1-(4- (trifluoromethoxy)benzyl)piperidin-4- yl)nicotinamide

495 N-(1-(4-methoxybenzyl)piperidin-4-yl)-6- (4-(4-(pentafluorosulfanyl)phenoxy)piperidine-1- carbonyl)nicotinamide

496 N-(6-(4-fluorophenoxy)pyridin-3-yl)-6-(4-(4-(pentafluorosulfanyl)phenoxy)piperidine- 1-carbonyl)nicotinamide

497 N-(6-(4-cyanophenoxy)pyridin-3-yl)-6-(4-(4-(pentafluorosulfanyl)phenoxy)piperidine- 1-carbonyl)nicotinamide

498 N-(1-(4-cyanobenzyl)-3,3-difluoropiperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1- carbonyl)nicotinamide

For simplicity, chemical moieties are defined and referred to throughoutprimarily as univalent chemical moieties (for example, alkyl, aryl,etc.). Nevertheless, such terms are also used to convey correspondingmultivalent moieties under the appropriate structural circumstancesclear to those skilled in the art. For example, while an “alkyl” moietycan refer to a monovalent radical (for example CH₃—CH₂—), in somecircumstances a bivalent linking moiety can be “alkyl,” in which casethose skilled in the art will understand the alkyl to be a divalentradical (for example the C₂ alkylene —CH₂—CH₂— may be described as a C₂alkyl group), which is equivalent to the term “alkylene.” (Similarly, incircumstances in which a divalent moiety is required and is stated asbeing “aryl,” those skilled in the art will understand that the term“aryl” refers to the corresponding divalent moiety, arylene). All atomsare understood to have their normal number of valences for bondformation (i.e., 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 for S,depending on the oxidation state of the S). Nitrogens in the presentlydisclosed compounds can be hypervalent, for example, an N-oxide ortetrasubstituted ammonium salt. On occasion a moiety may be defined, forexample, as (A)_(a)-B—, wherein a is 0 or 1. In such instances, when ais 0 the moiety is B— and when a is 1 the moiety is A-B—.

As used herein, the term “alkyl” includes alkyl, alkenyl and alkynylgroups of a designed number of carbon atoms, desirably from 1 to about12 carbons (i.e., inclusive of 1 and 12). The term “C_(m)-C_(n) alkyl”means an alkyl group having from m to n carbon atoms (i.e., inclusive ofm and n). The term “C_(m)-C_(n) alkyl” means an alkyl group having fromm to n carbon atoms. For example, “C₁-C₆ alkyl” is an alkyl group havingfrom one to six carbon atoms. Alkyl and alkyl groups may be straight orbranched and depending on context, may be a monovalent radical or adivalent radical (i.e., an alkylene group). In the case of an alkyl oralkyl group having zero carbon atoms (i.e., “C₀ alkyl”), the group issimply a single covalent bond if it is a divalent radical or is ahydrogen atom if it is a monovalent radical. For example, the moiety“—(C₀-C₆ alkyl)-Ar” signifies connection of an optionally substitutedaryl through a single bond or an alkylene bridge having from 1 to 6carbons. Examples of “alkyl” include, for example, methyl, ethyl,propyl, isopropyl, butyl, iso-, sec- and tert-butyl, pentyl, hexyl,heptyl, 3-ethylbutyl, 3-hexenyl and propargyl. If the number of carbonatoms is not specified, the subject “alkyl” or “alkyl” moiety has from 1to 12 carbons.

The term “haloalkyl” is an alkyl group substituted with one or morehalogen atoms, for example F, Cl, Br and I. A more specific term, forexample, “fluoroalkyl” is an alkyl group substituted with one or morefluorine atoms. Examples of “fluoroalkyl” include fluoromethyl,difluoromethyl, trifluoromethyl, pentafluoroethyl, hexafluoroisopropyland the like. In certain embodiments of the compounds disclosed herein,each haloalkyl is a fluoroalkyl.

The term “aryl” represents an aromatic carbocyclic ring system having asingle ring (for example, phenyl) which is optionally fused to otheraromatic hydrocarbon rings or non-aromatic hydrocarbon rings. “Aryl”includes ring systems having multiple condensed rings and in which atleast one is aromatic, (for example, 1,2,3,4-tetrahydronaphthyl,naphthyl). Examples of aryl groups include phenyl, 1-naphthyl,2-naphthyl, indanyl, indenyl, dihydronaphthyl, fluorenyl, tetralinyl,2,3-dihydrobenzofuranyl and 6,7,8,9-tetrahydro-5H-benzo[a]cycloheptenyl.The aryl groups herein are unsubstituted or, when specified as“optionally substituted”, can unless stated otherwise be substituted inone or more substitutable positions with various groups, as describedbelow.

The term “heteroaryl” refers to an aromatic ring system containing atleast one heteroatom selected from nitrogen, oxygen and sulfur in anaromatic ring. The heteroaryl may be fused to one or more cycloalkyl orheterocycloalkyl rings. Examples of heteroaryl groups include, forexample, pyridyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl,indolinyl, pyridazinyl, pyrazinyl, isoindolyl, isoquinolyl,quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl,pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl,benzimidazolyl, benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl,thiadiazolyl, benzo[1,4]oxazinyl, triazolyl, tetrazolyl, isothiazolyl,naphthyridinyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl,isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl,isobenzothienyl, benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl,benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, pteridinyl,benzothiazolyl, imidazopyridinyl, imidazothiazolyl,dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl,dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, chromonyl,chromanonyl, pyridinyl-N-oxide, tetrahydroquinolinyl, dihydroquinolinyl,dihydroquinolinonyl, dihydroisoquinolinonyl, dihydrocoumarinyl,dihydroisocoumarinyl, isoindolinonyl, benzodioxanyl, benzoxazolinonyl,pyrrolyl N-oxide, pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinylN-oxide, quinolinyl N-oxide, indolyl N-oxide, indolinyl N-oxide,isoquinolyl N-oxide, quinazolinyl N-oxide, quinoxalinyl N-oxide,phthalazinyl N-oxide, imidazolyl N-oxide, isoxazolyl N-oxide, oxazolylN-oxide, thiazolyl N-oxide, indolizinyl N-oxide, indazolyl N-oxide,benzothiazolyl N-oxide, benzimidazolyl N-oxide, pyrrolyl N-oxide,oxadiazolyl N-oxide, thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolylN-oxide, benzothiopyranyl S-oxide, benzothiopyranyl S,S-dioxide.Preferred heteroaryl groups include pyridyl, pyrimidyl, quinolinyl,indolyl, pyrrolyl, furanyl, thienyl and imidazolyl, pyrazolyl,indazolyl, thiazolyl and benzothiazolyl. In certain embodiments, eachheteroaryl is selected from pyridyl, pyrimidinyl, pyridazinyl,pyrazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl,furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl,tetrazolyl, isothiazolyl, pyridinyl-N-oxide, pyrrolyl N-oxide,pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, imidazolylN-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolyl N-oxide,pyrrolyl N-oxide, oxadiazolyl N-oxide, thiadiazolyl N-oxide, triazolylN-oxide, and tetrazolyl N-oxide. Preferred heteroaryl groups includepyridyl, pyrimidyl, quinolinyl, indolyl, pyrrolyl, furanyl, thienyl,imidazolyl, pyrazolyl, indazolyl, thiazolyl and benzothiazolyl. Theheteroaryl groups herein are unsubstituted or, when specified as“optionally substituted”, can unless stated otherwise be substituted inone or more substitutable positions with various groups, as describedbelow.

The term “heterocycloalkyl” refers to a non-aromatic ring or ring systemcontaining at least one heteroatom that is preferably selected fromnitrogen, oxygen and sulfur, wherein said heteroatom is in anon-aromatic ring. The heterocycloalkyl may be saturated (i.e., aheterocycloalkyl) or partially unsaturated (i.e., a heterocycloalkenyl).The heterocycloalkyl ring is optionally fused to other heterocycloalkylrings and/or non-aromatic hydrocarbon rings and/or phenyl rings. Incertain embodiments, the heterocycloalkyl groups have from 3 to 7members in a single ring. In other embodiments, heterocycloalkyl groupshave 5 or 6 members in a single ring. Examples of heterocycloalkylgroups include, for example, azabicyclo[2.2.2]octyl (in each case also“quinuclidinyl” or a quinuclidine derivative), azabicyclo[3.2.1]octyl,morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinylS,S-dioxide, 2-oxazolidonyl, piperazinyl, homopiperazinyl,piperazinonyl, pyrrolidinyl, azepanyl, azetidinyl, pyrrolinyl,tetrahydropyranyl, piperidinyl, tetrahydrofuranyl, tetrahydrothienyl,3,4-dihydroisoquinolin-2(1H)-yl, isoindolindionyl, homopiperidinyl,homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S,S-dioxide,oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl,dihydropyridinyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl,imidazolidonyl, tetrahydrothienyl S-oxide, tetrahydrothienyl S,S-dioxideand homothiomorpholinyl S-oxide. Especially desirable heterocycloalkylgroups include morpholinyl, 3,4-dihydroisoquinolin-2(1H)-yl,tetrahydropyranyl, piperidinyl, aza-bicyclo[2.2.2]octyl,γ-butyrolactonyl (i.e., an oxo-substituted tetrahydrofuranyl),γ-butryolactamyl (i.e., an oxo-substituted pyrrolidine), pyrrolidinyl,piperazinyl, azepanyl, azetidinyl, thiomorpholinyl, thiomorpholinylS,S-dioxide, 2-oxazolidonyl, imidazolidonyl, isoindolindionyl,piperazinonyl. The heterocycloalkyl groups herein are unsubstituted or,when specified as “optionally substituted”, can unless stated otherwisebe substituted in one or more substitutable positions with variousgroups, as described below.

The term “cycloalkyl” refers to a non-aromatic carbocyclic ring or ringsystem, which may be saturated (i.e., a cycloalkyl) or partiallyunsaturated (i.e., a cycloalkenyl). The cycloalkyl ring optionally fusedto or otherwise attached (for example, bridged systems) to othercycloalkyl rings. Preferred cycloalkyl groups have from 3 to 7 membersin a single ring. More preferred cycloalkyl groups have 5 or 6 membersin a single ring. Examples of cycloalkyl groups include, for example,cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, tetrahydronaphthyl andbicyclo[2.2.1]heptane. The cycloalkyl groups herein are unsubstitutedor, when specified as “optionally substituted”, may be substituted inone or more substitutable positions with various groups.

The term “oxa” means a divalent oxygen radical in a chain, sometimesdesignated as —O—.

The term “oxo” means a doubly bonded oxygen, sometimes designated as ═Oor for example in describing a carbonyl “C(O)” may be used to show anoxo substituted carbon.

The term “electron withdrawing group” means a group that withdrawselectron density from the structure to which it is attached than would asimilarly-attached hydrogen atom. For example, electron withdrawinggroups can be selected from the group consisting of halo, cyano, —(C₁-C₄fluoroalkyl), —O—(C₁-C₄ fluoroalkyl), —C(O)—(C₀-C₄ alkyl), —C(O)O—(C₀-C₄alkyl), —C(O)N(C₀-C₄ alkyl)(C₀-C₄ alkyl), —S(O)₂O—(C₀-C₄ alkyl), —SF₅,NO₂ and —C(O)—Hca in which the Hca includes a nitrogen atom to which the—C(O)— is bound, in which no alkyl, fluoroalkyl or heterocycloalkyl issubstituted with an aryl, heteroaryl, cycloalkyl orheterocycloalkyl-containing group.

The term “substituted,” when used to modify a specified group orradical, means that one or more hydrogen atoms of the specified group orradical are each, independently of one another, replaced with the sameor different substituent groups as defined below.

Substituent groups for substituting for hydrogens on saturated carbonatoms in the specified group or radical are, unless otherwise specified,—R⁶⁰, halo, —O⁻M⁺, ═O, —OR⁷⁰, —SR⁷⁰, —S⁻M⁺, ═S, —NR⁸⁰R⁸⁰, ═NR⁷⁰,═N—OR⁷⁰, trihalomethyl, —CF₃, —CN, —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃,—SO₂R⁷⁰, —SO₂O⁻M⁺, —SO₂OR⁷⁰, —OSO₂R⁷⁰, —OSO₂O⁻M⁺, —OSO₂OR⁷⁰,—P(O)(O⁻)₂(M⁺)₂, —P(O)(OR⁷⁰)O⁻M⁺, —P(O)(OR⁷⁰)₂, —C(O)R⁷⁰, —C(S)R⁷⁰,—C(NR⁷⁰)R⁷⁰, —C(O)O⁻M⁺, —C(O)OR⁷⁰, —C(S)OR⁷⁰, —C(O)NR⁸⁰R⁸⁰,—C(NR⁷⁰)NR⁸⁰R⁸⁰, —OC(O)R⁷⁰, —OC(S)R⁷⁰, —OC(O)O⁻M⁺, —OC(O)OR⁷⁰,—OC(S)OR⁷⁰, —NR⁷⁰C(O)R⁷⁰, —NR⁷⁰C(S)R⁷⁰, —NR⁷⁰CO₂ ⁻M⁺, —NR⁷⁰CO₂R⁷⁰,—NR⁷⁰C(S)OR⁷⁰, —NR⁷⁰C(O)NR⁸⁰R⁸⁰, —NR⁷⁰C(NR⁷⁰)R⁷⁰ and—NR⁷⁰C(NR⁷⁰)NR⁸⁰R⁸⁰. Each R⁶⁰ is independently selected from the groupconsisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl,heterocycloalkylalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl andheteroarylalkyl, each of which is optionally substituted with 1, 2, 3, 4or 5 groups selected from the group consisting of halo, —O⁻M⁺, ═O,—OR⁷¹, —SR⁷¹, —S⁻M⁺, ═S, —NR⁸¹R⁸¹, ═NR⁷¹, ═N—OR⁷¹, trihalomethyl, —CF₃,—CN, —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃, —SO₂R⁷¹, —SO₂O⁻M⁺, —OSO₂R⁷¹,—OSO₂R⁷¹, —OSO₂O⁻M⁺, —OSO₂OR⁷¹, —P(O)(O⁻)²(M⁺)₂, —P(O)(OR⁷¹)O⁻M⁺,—P(O)(OR⁷¹)₂, —C(O)R⁷¹, —C(S)R⁷¹, —C(NR⁷¹)R⁷¹, —C(O)O⁻M⁻, —C(O)OR⁷¹,—C(S)OR⁷¹, —C(O)NR⁸¹R⁸¹, —C(NR⁷¹)NR⁸¹R⁸¹, —OC(O)R⁷¹, —OC(S)R⁷¹,—OC(O)O⁻M⁺, —OC(O)OR⁷¹, —OC(S)OR⁷¹, —NR⁷¹C(O)R⁷¹, —NR⁷¹C(S)R⁷¹, —NR⁷¹CO₂⁻M⁺, —NR⁷¹CO₂R⁷¹, —NR⁷¹C(S)OR⁷¹, —NR⁷¹C(O)R⁷¹, —NR⁷¹C(S)R⁷¹, —NR⁷¹CO₂⁻and —NR⁷¹C(NR⁷¹)NR⁸¹R⁸¹. Each R⁷⁰ is independently hydrogen or R⁶⁰;each R⁸⁰ is independently R⁷⁰ or alternatively, two R⁸⁰'s, takentogether with the nitrogen atom to which they are bonded, form a 5-, 6-or 7-membered heterocycloalkyl which may optionally include from 1 to 4of the same or different additional heteroatoms selected from the groupconsisting of O, N and S, of which N may have —H or C₁-C₃ alkylsubstitution; and each M⁺ is a counter ion with a net single positivecharge. Each R⁷¹ is independently hydrogen or R⁶¹, in which R⁶¹ isalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl,cycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl, eachof which is optionally substituted with 1, 2, 3, 4 or 5 groups selectedfrom the group consisting of halo, —O⁻M⁺, ═O, —OR⁷², —SR⁷², —S⁻M⁺, ═S,—NR⁸²R⁸², ═NR⁷², ═N—OR⁷², trihalomethyl, —CF₃, —CN, —OCN, —SCN, —NO,—NO₂, —N₂, —N₃, —SO₂R⁷¹, —SO₂O⁻M⁺, —SO₂OR⁷², —OSO₂R⁷², —OSO₂O⁻M⁺,—OSO₂OR⁷², —P(O)(O⁻)₂(M⁺)₂, —P(O)(OR⁷²)O⁻M⁺, —P(O)(OR⁷²)₂, —C(O)R⁷²,—C(S)R⁷², —C(NR⁷²)R⁷², —C(O)O⁻M⁺, —C(O)OR⁷², —C(S)OR⁷², —C(O)NR⁸²R⁸²(NR⁷²)NR⁸²R⁸², —OC(O)R⁷², —OC(S)R⁷², —OC(O)O⁻M⁺, —OC(O)OR⁷², —OC(S)OR⁷²,—NR⁷²C(O)R⁷², —NR⁷²C(S)R⁷², —NR⁷²CO₂ ⁻M⁺, —NR⁷²CO₂R⁷², —NR⁷²C(S)OR⁷²,—NR⁷²C(O)NR⁸²R⁸², —NR⁷²C(NR⁷²)R⁷² and —NR⁷²C(NR⁷²)NR⁸²R⁸²; and each R⁸¹is independently R⁷¹ or alternatively, two R⁸¹s, taken together with thenitrogen atom to which they are bonded, form a 5-, 6- or 7-memberedheterocycloalkyl which may optionally include from 1 to 4 of the same ordifferent additional heteroatoms selected from the group consisting ofO, N and S, of which N may have —H or C₁-C₃ alkyl substitution. Each R⁷²is independently hydrogen, (C₁-C₆ alkyl) or (C₁-C₆ fluoroalkyl); eachR⁸² is independently R⁷² or alternatively, two R⁸²s, taken together withthe nitrogen atom to which they are bonded, form a 5-, 6- or 7-memberedheterocycloalkyl which may optionally include 1, 2, 3 or 4 of the sameor different additional heteroatoms selected from the group consistingof O, N and S, of which N may have —H or C₁-C₃ alkyl substitution. EachM⁺ may independently be, for example, an alkali ion, such as K⁺, Na⁺,Li⁺; an ammonium ion, such as ⁺N(R⁶⁰)₄; or an alkaline earth ion, suchas [Ca²⁺]_(0.5), [Mg²⁺]_(0.5), or [Ba²⁺]_(0.5) (“subscript 0.5 means forexample that one of the counter ions for such divalent alkali earth ionscan be an ionized form of a presently disclosed compound and the other atypical counter ion such as chloride, or two ionized presently disclosedmolecules can serve as counter ions for such divalent alkali earth ions,or a doubly ionized compound can serve as the counter ion for suchdivalent alkali earth ions). As specific examples, —NR⁸⁰R⁸⁰ is meant toinclude —NH₂, —NH-alkyl, N-pyrrolidinyl, N-piperazinyl,4-methyl-piperazin-1-yl and N-morpholinyl. In certain embodiments, eachR⁶⁰ is H or (unsubstituted C₁-C₆ alkyl). In certain embodiments, eachR⁷⁰ is H or (unsubstituted C₁-C₆ alkyl). In certain embodiments, eachR⁸⁰ is H or (unsubstituted C₁-C₆ alkyl).

Substituent groups for hydrogens on unsaturated carbon atoms in“substituted” alkene, alkyne, aryl and heteroaryl groups are, unlessotherwise specified, —R⁶⁰, halo, —O⁻M⁺, —OR⁷⁰, —SR⁷⁰, —S⁻M⁺, —NR⁸⁰R⁸⁰,trihalomethyl, —CF₃, —OCN, —SCN, —NO, —NO₂, —SO₂R⁷⁰, —SO₃ ⁻M⁺, —SO₃R⁷⁰,—OSO₂R⁷⁰, —OSO₃ ⁻M⁺, —OSO₃R⁷⁰, —PO₃ ⁻²(M⁺)₂, —P(O)(OR⁷⁰)O⁻M⁺,—P(O)(OR⁷⁰)₂, —C(O)R⁷⁰, —C(S)R⁷⁰, —C(NR⁷⁰)R⁷⁰, —CO₂ ⁻M⁺, —CO₂R⁷⁰,—C(S)OR⁷⁰, —C(O)NR⁸⁰R⁸⁰, —C(NR⁷⁰)NR⁸⁰R⁸⁰, —OC(O)R⁷⁰, —OC(S)R⁷⁰, —OCO₂⁻M⁺, —OCO₂R⁷⁰, —OC(S)OR⁷⁰, —NR⁷⁰C(O)R⁷⁰, —NR⁷⁰C(S)R⁷⁰, —NR⁷⁰CO₂ ⁻M⁺,—NR⁷⁰CO₂R⁷⁰, —NR⁷⁰C(S)OR⁷⁰, —NR⁷⁰C(O)NR⁸⁰R⁸⁰, —NR⁷⁰C(NR⁷⁰)R⁷⁰ and—NR⁷⁰C(NR⁷⁰)NR⁸⁰R⁸⁰, where R⁶⁰, R⁷⁰, R⁸⁰ and M⁺ are as previouslydefined.

Substituent groups for hydrogens on nitrogen atoms in “substituted”heteroalkyl and heterocycloalkyl groups are, unless otherwise specified,—R⁶⁰, —O⁻M⁺, —OR⁷⁰, —SR⁷⁰, —S trihalomethyl, —CF₃, —CN, —NO, —NO₂,—S(O)₂R⁷⁰, —S(O)₂O⁻M⁺, —S(O)₂OR⁷⁰, —OS(O)₂R⁷⁰, —OS(O)₂O⁻M⁺, —OS(O)₂OR⁷⁰,—P(O)(O⁻)₂(M⁺)₂, —P(O)(OR⁷⁰)O⁻M⁺, —P(O)(OR⁷⁰)(OR⁷⁰), —C(O)R⁷⁰, —C(S)R⁷⁰,—C(NR⁷⁰)R⁷⁰, —C(O)OR⁷⁰, —C(S)OR⁷⁰, —C(O)NR⁸⁰R⁸⁰, —C(NR⁷⁰)NR⁸⁰R⁸⁰,—OC(O)R⁷⁰, —OC(S)R⁷⁰, —OC(O)OR⁷⁰, —OC(S)OR⁷⁰, —NR⁷⁰C(O)R⁷⁰,—NR⁷⁰C(S)R⁷⁰, —NR⁷⁰C(O)OR⁷⁰, —NR⁷⁰C(S)OR⁷⁰, —NR⁷⁰C(O)NR⁸⁰R⁸⁰,—NR⁷⁰C(NR⁷⁰)R⁷⁰ and —NR⁷⁰C(NR⁷⁰)NR⁸⁰R⁸⁰, where R⁶⁰, R⁷⁰, R⁸⁰ and M⁺ areas previously defined.

In certain embodiments as described above, the substituent groups oncarbon atoms can also or alternatively be —SF₅.

In certain embodiments of the compounds disclosed herein, a group thatis substituted has 1, 2, 3, or 4 substituents, 1, 2, or 3 substituents,1 or 2 substituents, or 1 substituent.

In certain embodiments, an “optionally substituted alkyl,” unlessotherwise specified, is substituted with halogen (e.g., F, Cl),unsubstituted (C₁-C₆ alkoxy) (e.g., methoxy, ethoxy), —(C₁-C₆haloalkoxy) (e.g., trifluoromethoxy), —SH, —S(unsubstituted C₁-C₆alkyl), —S(C₁-C₆ haloalkyl), —OH, —CN, —NO₂, —NH₂₅—NH(unsubstitutedC₁-C₄ alkyl), —N(unsubstituted C₁-C₄ alkyl)₂, —C(O)—NH₂,C(O)NH(unsubstituted C₁-C₄ alkyl), C(O)N(unsubstituted C₁-C₄ alkyl)₂,—C(O)OH, C(O)O(unsubstituted C₁-C₆ alkyl), —(NH)₀₋₁SO₂R³³,—(NH)₀₋₁COR³³, heterocycloalkyl optionally substituted with an(unsubstituted C₁-C₆ alkyl) and heteroaryl optionally substituted withan (unsubstituted C₁-C₆ alkyl), in which each R³³ is (unsubstitutedC₁-C₆ alkyl), (C₁-C₆ haloalkyl(unsubstituted C₃-C₈ cycloalkyl) or (C₃-C₈heterocycloalkyl) optionally substituted with an (unsubstituted C₁-C₆alkyl). In certain embodiments, “optionally substituted alkyl” is alsoor alternatively optionally substituted with —N₃ or —SF₅.

In certain embodiments, an “optionally substituted aryl,” unlessotherwise specified, is substituted with halogen (e.g., F, Cl),unsubstituted (C₁-C₆ alkoxy) (e.g., methoxy, ethoxy), —(C₁-C₆haloalkoxy) (e.g., trifluoromethoxy), —SH, —S(unsubstituted C₁-C₆alkyl), —S(C₁-C₆ haloalkyl), —OH, —CN, —NO₂, —NH₂₅—NH(unsubstitutedC₁-C₄ alkyl), —N(unsubstituted C₁-C₄ alkyl)₂, —C(O)—NH₂,C(O)NH(unsubstituted C₁-C₄ alkyl), C(O)N(unsubstituted C₁-C₄ alkyl)₂,—C(O)OH, C(O)O(unsubstituted C₁-C₆ alkyl), —(NH)₀₋₁SO₂R³³,—(NH)₀₋₁COR³³, heterocycloalkyl optionally substituted with an(unsubstituted C₁-C₆ alkyl) and heteroaryl optionally substituted withan (unsubstituted C₁-C₆ alkyl), in which each R³³ is (unsubstitutedC₁-C₆ alkyl), (C₁-C₆ haloalkyl(unsubstituted C₃-C₈ cycloalkyl) or (C₃-C₈heterocycloalkyl) optionally substituted with an (unsubstituted C₁-C₆alkyl). In certain embodiments, “optionally substituted aryl” is also oralternatively optionally substituted with —N₃ or —SF₅.

In certain embodiments, an “optionally substituted heteroaryl,” unlessotherwise specified, is substituted with halogen (e.g., F, Cl),unsubstituted (C₁-C₆ alkoxy) (e.g., methoxy, ethoxy), —(C₁-C₆haloalkoxy) (e.g., trifluoromethoxy), —SH, —S(unsubstituted C₁-C₆alkyl), —S(C₁-C₆ haloalkyl), —OH, —CN, —NO₂, —NH₂, —NH(unsubstitutedC₁-C₄ alkyl), —N(unsubstituted C₁-C₄ alkyl)₂, —C(O)—NH₂,C(O)NH(unsubstituted C₁-C₄ alkyl), C(O)N(unsubstituted C₁-C₄ alkyl)₂,—C(O)OH, C(O)O(unsubstituted C₁-C₆ alkyl), —(NH)₀₋₁SO₂R³³,—(NH)₀₋₁COR³³, heterocycloalkyl optionally substituted with an(unsubstituted C₁-C₆ alkyl) and heteroaryl optionally substituted withan (unsubstituted C₁-C₆ alkyl), in which each R³³ is (unsubstitutedC₁-C₆ alkyl), (C₁-C₆ haloalkyl(unsubstituted C₃-C₈ cycloalkyl) or (C₃-C₈heterocycloalkyl) optionally substituted with an (unsubstituted C₁-C₆alkyl). In certain embodiments, “optionally substituted heteroaryl” isalso or alternatively optionally substituted with —N₃ or —SF₅.

In certain embodiments, an “optionally substituted cycloalkyl,” unlessotherwise specified, is substituted with halogen (e.g., F, Cl),unsubstituted (C₁-C₆ alkoxy) (e.g., methoxy, ethoxy), —(C₁-C₆haloalkoxy) (e.g., trifluoromethoxy), —SH, —S(unsubstituted C₁-C₆alkyl), —S(C₁-C₆ haloalkyl), —OH, —CN, —NO₂, —NH₂, —NH(unsubstitutedC₁-C₄ alkyl), —N(unsubstituted C₁-C₄ alkyl)₂, —C(O)—NH₂,C(O)NH(unsubstituted C₁-C₄ alkyl), C(O)N(unsubstituted C₁-C₄ alkyl)₂,—C(O)OH, C(O)O(unsubstituted C₁-C₆ alkyl), —(NH)₀₋₁SO₂R³³,—(NH)₀₋₁COR³³, heterocycloalkyl optionally substituted with an(unsubstituted C₁-C₆ alkyl) and heteroaryl optionally substituted withan (unsubstituted C₁-C₆ alkyl), in which each R³³ is (unsubstitutedC₁-C₆ alkyl), (C₁-C₆ haloalkyl(unsubstituted C₃-C₈ cycloalkyl) or (C₃-C₈heterocycloalkyl) optionally substituted with an (unsubstituted C₁-C₆alkyl). In certain embodiments, “optionally substituted cycloalkyl” isalso or alternatively optionally substituted with —N₃ or —SF₅.

In certain embodiments, an “optionally substituted heterocycloalkyl,”unless otherwise specified, is substituted with halogen (e.g., F, Cl),unsubstituted (C₁-C₆ alkoxy) (e.g., methoxy, ethoxy), —(C₁-C₆haloalkoxy) (e.g., trifluoromethoxy), —SH, —S(unsubstituted C₁-C₆alkyl), —S(C₁-C₆ haloalkyl), —OH, —CN, —NO₂, —NH₂, —NH(unsubstitutedC₁-C₄ alkyl), —N(unsubstituted C₁-C₄ alkyl)₂, —C(O)—NH₂,C(O)NH(unsubstituted C₁-C₄ alkyl), C(O)N(unsubstituted C₁-C₄ alkyl)₂,—C(O)OH, C(O)O(unsubstituted C₁-C₆ alkyl), —(NH)₀₋₁SO₂R³³,—(NH)₀₋₁COR³³, heterocycloalkyl optionally substituted with an(unsubstituted C₁-C₆ alkyl) and heteroaryl optionally substituted withan (unsubstituted C₁-C₆ alkyl), in which each R³³ is (unsubstitutedC₁-C₆ alkyl), (C₁-C₆ haloalkyl(unsubstituted C₃-C₈ cycloalkyl) or (C₃-C₈heterocycloalkyl) optionally substituted with an (unsubstituted C₁-C₆alkyl). In certain embodiments, “optionally substitutedheterocycloalkyl” is also or alternatively optionally substituted with—N₃ or —SF₅.

The compounds disclosed herein can also be provided as pharmaceuticallyacceptable salts. The term “pharmaceutically acceptable salts” or “apharmaceutically acceptable salt thereof” refer to salts prepared frompharmaceutically acceptable non-toxic acids or bases including inorganicacids and bases and organic acids and bases. If the compound is basic,salts may be prepared from pharmaceutically acceptable non-toxic acids.Such salts may be, for example, acid addition salts of at least one ofthe following acids: benzenesulfonic acid, citric acid, α-glucoheptonicacid, D-gluconic acid, glycolic acid, lactic acid, malic acid, malonicacid, mandelic acid, phosphoric acid, propanoic acid, succinic acid,sulfuric acid, tartaric acid (d, l, or dl), tosic acid (toluenesulfonicacid), valeric acid, palmitic acid, pamoic acid, sebacic acid, stearicacid, lauric acid, acetic acid, adipic acid, carbonic acid,4-chlorobenzenesulfonic acid, ethanedisulfonic acid, ethylsuccinic acid,fumaric acid, galactaric acid (mucic acid), D-glucuronic acid,2-oxo-glutaric acid, glycerophosphoric acid, hippuric acid, isethionicacid (ethanolsulfonic acid), lactobionic acid, maleic acid,1,5-naphthalene-disulfonic acid, 2-naphthalene-sulfonic acid, pivalicacid, terephthalic acid, thiocyanic acid, cholic acid, n-dodecylsulfate, 3-hydroxy-2-naphthoic acid, 1-hydroxy-2-naphthoic acid, oleicacid, undecylenic acid, ascorbic acid, (+)-camphoric acid,d-camphorsulfonic acid, dichloroacetic acid, ethanesulfonic acid, formicacid, hydriodic acid, hydrobromic acid, hydrochloric acid,methanesulfonic acid, nicotinic acid, nitric acid, orotic acid, oxalicacid, picric acid, L-pyroglutamic acid, saccharine, salicylic acid,gentisic acid, and/or 4-acetamidobenzoic acid.

The compounds described herein can also be provided in prodrug form.“Prodrug” refers to a derivative of an active compound (drug) thatrequires a transformation under the conditions of use, such as withinthe body, to release the active drug. Prodrugs are frequently, but notnecessarily, pharmacologically inactive until converted into the activedrug. Prodrugs are typically obtained by masking a functional group inthe drug believed to be in part required for activity with a progroup(defined below) to form a promoiety which undergoes a transformation,such as cleavage, under the specified conditions of use to release thefunctional group, and hence the active drug. The cleavage of thepromoiety can proceed spontaneously, such as by way of a hydrolysisreaction, or it can be catalyzed or induced by another agent, such as byan enzyme, by light, by acid, or by a change of or exposure to aphysical or environmental parameter, such as a change of temperature.The agent can be endogenous to the conditions of use, such as an enzymepresent in the cells to which the prodrug is administered or the acidicconditions of the stomach, or it can be supplied exogenously. A widevariety of progroups, as well as the resultant promoieties, suitable formasking functional groups in the active drugs to yield prodrugs arewell-known in the art. For example, a hydroxyl functional group can bemasked as a sulfonate, ester or carbonate promoiety, which can behydrolyzed in vivo to provide the hydroxyl group. An amino functionalgroup can be masked as an amide, carbamate, imine, urea, phosphenyl,phosphoryl or sulfenyl promoiety, which can be hydrolyzed in vivo toprovide the amino group. A carboxyl group can be masked as an ester(including silyl esters and thioesters), amide or hydrazide promoiety,which can be hydrolyzed in vivo to provide the carboxyl group. Otherspecific examples of suitable progroups and their respective promoietieswill be apparent to those of skill in the art.

The compounds disclosed herein can also be provided as N-oxides.

The presently disclosed compounds, salts, prodrugs and N-oxides can beprovided, for example, in solvate or hydrate form.

Compounds can be assayed for binding to a membrane-bound adiponectinreceptor by performing a competitive binding assay with adiponectin. Inone such procedure, HEK 293 cellular membrane is coated onto a COSTAR384 plate, which is then blocked with 1% casein. Polyhistidine-taggedglobular adiponectin and a candidate compound is incubated with themembrane in HEPES buffer. Unbound ligands are washed away and the degreeof binding of the adiponectin is determined using horseradishperoxidase-conjugated anti-polyhistidine. Compounds that compete withadiponectin binding to the membrane (i.e., give a reduced signalcompared to a control performed without a candidate compound) can bechosen as hits and further screened using the below-described functionalassays to identify adiponectin receptor agonists.

An in-cell western assay can be performed to demonstrate the activationof the AMPK pathway in human liver cells by globular adiponectin usingglutathione S-transferase (GST). AMPK activity can be measured by therelative concentration of phosphorylated acetyl Co-A carboxylase, whichis one of the products of AMPK. An increase in pACC correlates with anincrease in the rate of fatty acid oxidation.

The compounds of structural formulae (I)-(LXXXVI) can be administered,for example, orally, topically, parenterally, by inhalation or spray orrectally in dosage unit formulations containing one or morepharmaceutically acceptable carriers, diluents or excipients. The termparenteral as used herein includes percutaneous, subcutaneous,intravascular (for example, intravenous), intramuscular, or intrathecalinjection or infusion techniques and the like.

Pharmaceutical compositions can be made using the presently disclosedcompounds. For example, in one embodiment, a pharmaceutical compositionincludes a pharmaceutically acceptable carrier, diluent or excipient,and compound as described above with reference to structural formulae(I)-(LXXXVI).

In the pharmaceutical compositions disclosed herein, one or morecompounds of structural formulae (I)-(LXXXVI) may be present inassociation with one or more pharmaceutically acceptable carriers,diluents or excipients, and, if desired, other active ingredients. Thepharmaceutical compositions containing compounds of structural formulae(I)-(LXXXVI) may be in a form suitable for oral use, for example, astablets, troches, lozenges, aqueous or oily suspensions, dispersiblepowders or granules, emulsion, hard or soft capsules, or syrups orelixirs.

Compositions intended for oral use can be prepared according to anysuitable method for the manufacture of pharmaceutical compositions andsuch compositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents andpreservative agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients that aresuitable for the manufacture of tablets. These excipients can be forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, corn starch, or alginic acid;binding agents, for example starch, gelatin or acacia, and lubricatingagents, for example magnesium stearate, stearic acid or talc. Thetablets can be uncoated or they can be coated by known techniques. Insome cases such coatings can be prepared by suitable techniques to delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearate canbe employed.

Formulations for oral use can also be presented as hard gelatincapsules, wherein the active ingredient is mixed with an inert soliddiluent, for example, calcium carbonate, calcium phosphate or kaolin, oras soft gelatin capsules wherein the active ingredient is mixed withwater or an oil medium, for example peanut oil, liquid paraffin or oliveoil.

Formulations for oral use can also be presented as lozenges.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients can be suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents such as a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions can be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents and flavoring agents may beadded to provide palatable oral preparations. These compositions may bepreserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents orsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, can also be present.

Pharmaceutical compositions can also be in the form of oil-in-wateremulsions. The oily phase can be a vegetable oil or a mineral oil ormixtures of these. Suitable emulsifying agents can benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions can also containsweetening and flavoring agents.

Syrups and elixirs can be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol, glucose or sucrose. Suchformulations can also contain a demulcent, a preservative, flavoring,and coloring agents. The pharmaceutical compositions can be in the formof a sterile injectable aqueous or oleaginous suspension. Thissuspension can be formulated according to the known art using thosesuitable dispersing or wetting agents and suspending agents that havebeen mentioned above. The sterile injectable preparation can also be asterile injectable solution or suspension in a non-toxic parentallyacceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that can beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils can be employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid find use in the preparation of injectables.

Compounds of structural formulae (I)-(LXXXVI) can be formulated intolotions, oils or powders for application to the skin according tocertain methods described below.

Compounds of structural formulae (I)-(LXXXVI) can also be administeredin the form of suppositories, for example, for rectal administration ofthe drug. These compositions can be prepared by mixing the compound witha suitable non-irritating excipient that is solid at ordinarytemperatures but liquid at the rectal temperature and will thereforemelt in the rectum to release the drug. Such materials include cocoabutter and polyethylene glycols.

Compounds of structural formula (I)-(LXXXVI) can also be administeredparenterally in a sterile medium. The drug, depending on the vehicle andconcentration used, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

The compounds disclosed herein can be made using procedures familiar tothe person of ordinary skill in the art and as described herein. Forexample, compounds of structural formula (I) can be prepared accordingto Schemes 1-6, below, or analogous synthetic schemes:

Referring to Scheme 1, a pyridinedicarboxylic acid monomethyl ester (i),for example, is coupled with an amine (here a substituted1-benzoylpiperidine-4-amine) to form a carboxymethyl-substitutedpyridinecarboxamide (ii). The ester is saponified to form thecorresponding carboxylic acid (iii), which is then coupled with asuitable amine (in this case, a substituted 1-benzylpiperazine) to formCompound 4 of Table 1.

Referring to Scheme 2, a bromopyridinedicarboxylic acid, for example, iscoupled with an amine (here a substituted 1-benzylpiperidine-4-amine) toform a bromo-substituted pyridinecarboxamide (iv), which is then coupledwith a suitable amine (in this case, a substituted 4-phenoxypiperidine)using a palladium catalyst to form Compound 17 of Table 1.

Referring to Scheme 3, a pyridinedicarboxylic acid monomethyl ester (v),for example, is coupled with an amine (here a substituted1-benzylpiperidine-4-amine) to form a carboxymethyl-substitutedpyridinecarboxamide (vi). The ester is saponified to form thecorresponding carboxylic acid (vii), which is then coupled with asuitable amine (in this case, a substituted 4-benzoylpiperidine) to formCompound 160 of Table 1.

Referring to Scheme 4, a pyridine dicarboxylic acid (viii), for example,is coupled with one equivalent of an amine (here, a substituted1-benzylepiperizine), then with methanol andtrimethylsilyl(diazomethane) to form a carbomethoxy-substitutedpyridinecarboxamide (ix), which is saponified to give a carboxylicacid-substituted pyridinecarboxamide (x). An amine (in this case,1-phenylpiperazine) is coupled with the carboxylic acid-substitutedpyridinecarboxamide (x) to form Compound 94 of Table 1.

Referring to Scheme 5, a bromopyridinecarboxamide (xi) is coupled with asubstituted 1-benzylpiperidine-4-carboxamide using a palladium catalystto form Compound 46 of Table 1. Reactions of this general type aredescribed in more detail, for example, in Wrona, Iwona E. et al.,Journal of Organic Chemistry (2010), 75(9), 2820-2835.

Scheme 6 describes a preparation that can be used to makegem-dimethylpiperazines for use in making compounds analogous toCompound 125 of Table 1. A piperazin-2-one is singly protected withtrityl chloride, then coupled with an appropriate bromide (here, asubstituted benzyl bromide) to form a 4-protected 1-(substitutedbenzyl)piperazin-2-one. The oxo is convered to a gem-dimethyl usingGrignard chemistry, then the trityl is removed to yield the desiredgem-dimethyl piperazine. Details are provided in the Examples below, andin Xiao, K-J.; Luo, J-M.; Ye, K-Y.; Wang, Y.; Huang, P-Q. Angew. Chem.Int. Ed. 2010, 49, 3037-3040.

One of skill in the art can adapt the reaction sequences of Schemes 1-6to fit the desired target molecule. Of course, in certain situations oneof skill in the art will use different reagents to affect one or more ofthe individual steps or to use protected versions of certain of thesubstituents. Additionally, one skilled in the art would recognize thatcompounds of structural formulae (I)-(LXXXVI) can be synthesized usingdifferent routes altogether.

Compounds suitable for use in the presently disclosed pharmaceuticalcompositions include compounds of Table 1, above. These compounds can bemade according to the general scheme described above, for example usinga procedure similar to that described below in the Examples.

While not intending to be bound by theory, the inventors surmise thatcompounds of structural formulae (I)-(LXXXVI) activate the AMPK pathway.Activation of the AMPK pathway has the effect of increasing glucoseuptake, decreasing glycogen synthesis and increasing fatty acidoxidation, thereby reducing glycogen, intracellular triglyceride andfatty acid concentration and causing an increase in insulin sensitivity.Because they activate the AMPK pathway, compounds of structural formulae(I)-(LXXXVI) should also inhibit the inflammatory processes which occurduring the early phases of atherosclerosis. Accordingly, compounds ofstructural formulae (I)-(LXXXVI) can be useful in the treatment of typeII diabetes and in the treatment and prevention of atherosclerosis,cardiovascular disease, obesity and non-alcoholic fatty liver disease.

In one aspect and without limitation to theory, the present compoundsexert AMPK activating activity by binding to an adiponectin receptor,acting as effective adiponectin mimetics. Adiponectin is a proteinhormone exclusively expressed in and secreted from adipose tissue and isthe most abundant adipose-specific protein. Adiponectin has beenimplicated in the modulation of glucose and lipid metabolism ininsulin-sensitive tissues. Decreased circulating adiponectin levels havebeen demonstrated in some insulin-resistant states, such as obesity andtype 2 diabetes mellitus and also in patients with coronary arterydisease, atherosclerosis and hypertension. Adiponectin levels arepositively correlated with insulin sensitivity, HDL (high densitylipoprotein) levels and insulin stimulated glucose disposal andinversely correlated with adiposity and glucose, insulin andtriglyceride levels. Thiazolidinedione drugs, which enhance insulinsensitivity through activation of the peroxisome proliferator-activatedreceptor-γ, increase endogenous adiponectin production in humans.

Adiponectin binds its receptors in liver and skeletal muscle and therebyactivates the AMPK pathway. Similarly, in one aspect, the presentcompounds act as adiponectin receptor agonists. Adiponectin receptors 1and 2 are membrane-bound proteins found in skeletal muscle and livertissue.

Accordingly, another aspect of the present disclosure relates to amethod of activating the AMPK pathway. According to this aspect, amethod for activating the AMPK pathway in a cell includes contacting thecell with an effective amount of a compound, pharmaceutically acceptablesalt, prodrug, N-oxide (or solvate or hydrate thereof) or composition ofsuch a compound described above, such as a compound of one of formulas(I)-(LXXXVI).

In one embodiment, a method of increasing fatty acid oxidation in a cellincludes contacting the cell with an effective amount of a compound,pharmaceutically acceptable salt, prodrug, N-oxide (or solvate orhydrate thereof) or composition of such a compound described above, suchas a compound of one of formulas (I)-(LXXXVI). Acetyl Co-A carboxylase(ACC) catalyzes the formation of malonyl Co-A, a potent inhibitor offatty acid oxidation; phosphorylation of ACC greatly reduces itscatalytic activity, thereby reducing the concentration of malonyl Co-Aand increasing the rate of fatty acid oxidation. Because the presentlydisclosed compounds can increase the rate of phosphorylation of ACC,they can reduce the inhibition of fatty acid oxidation and thereforeincrease its overall rate.

In another embodiment, a method of decreasing glycogen concentration ina cell includes contacting the cell with an effective amount of acompound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvateor hydrate thereof) or composition of such a compound described above,such as a compound of one of formulas (I)-(LXXXVI).

In another embodiment, a method of increasing glucose uptake in a cellincludes contacting the cell with an effective amount of a compound,pharmaceutically acceptable salt, prodrug, N-oxide (or solvate orhydrate thereof) or composition of such a compound described above, suchas a compound of one of formulas (I)-(LXXXVI).

In another embodiment, a method of reducing triglyceride levels in asubject includes administering to the subject an effective amount of acompound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvateor hydrate thereof) or composition of such a compound described above,such as a compound of one of formulas (I)-(LXXXVI).

In another embodiment, a method of increasing insulin sensitivity of asubject includes administering to the subject an effective amount of acompound, pharmaceutically acceptable salt prodrug, N-oxide (or solvateor hydrate thereof) or composition of such a compound described above,such as a compound of one of formulas (I)-(LXXXVI).

Accordingly, the compounds and compositions disclosed herein can be usedto treat a variety of metabolic disorders. For example, in oneembodiment, a method of treating type II diabetes in a subject in needof such treatment includes administering to the subject an effectiveamount of a compound, pharmaceutically acceptable salt, prodrug,solvate, hydrate, N-oxide or composition described above. In anotherembodiment, a method of treating or preventing atherosclerosis orcardiovascular disease in a subject includes administering to thesubject an effective amount of a compound, pharmaceutically acceptablesalt, prodrug prodrug, N-oxide (or solvate or hydrate thereof) orcomposition of such a compound described above, such as compound of oneof formulas (I)-(LXXXVI).

As described above, the compounds disclosed herein can act as activatorsof the AMPK pathway. Accordingly, in another embodiment, a methodcomprises modulating the AMPK pathway (either in vitro or in vivo) bycontacting a cell with a compound, pharmaceutically acceptable salt,prodrug, N-oxide (or solvate or hydrate thereof) or compositiondescribed above, or administering a compound, pharmaceuticallyacceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) orcomposition described above to a mammal (for example, a human) in anamount sufficient to modulate the AMPK activity and study the effectsthereby induced. Such methods are useful for studying the AMPK pathwayand its role in biological mechanisms and disease states both in vitroand in vivo.

In certain embodiments, the compounds disclosed herein affect lipidsignaling pathways. For example, in some embodiments, the compoundsup-regulate ceramidase activity. Ceramide is a central player insphingolipid metabolism, and is the immediate precursor ofsphingomyelins and glycosphingolipids as well as the bioactive productssphingosine and sphingosine-1-phosphate. Moreover, endogenous ceramideitself mediates, at least in part, the actions of a variety of stimulion cell differentiation, apoptosis, and growth suppression. Ceramide isdeacylated by ceramidase to form sphingosine, which is in turnphosphorylated to sphingosine-1-phosphate by sphingosine kinase.

Elevated ceramide levels have been shown to induce cell apoptosis,differentiation and senescence. Moreover, elevated ceramide levels arelinked to a variety of diseases and disorders, including, for example,Batten's disease, inflammatory bowel diseases, diffuse intravascularcoagulation, fever, protein catabolism and/or lipid depletion,hepatosplenomegaly associated with inflammatory or metabolic liverdiseases, endomyocarditis, endolithial cell and leucocyte activation,capillary thrombosis, meningo-encephalitis due to infectious agents,complications in organ transplantation, rheumatoid arthritis andconnective tissue diseases, autoimmune diseases, hyperthyroidism, damageby radiation/chemotherapy agents and chronic fatigue syndrome.

Up-regulating ceramidase function (and therefore reducing theconcentration of ceramide) can be used to treat disorders involvingdeficient cell proliferation (growth) or in which cell proliferation isotherwise desired, for example, degenerative disorders, growthdeficiencies, lesions, physical trauma, and diseases in which ceramideaccumulates within cells, such as Fabry disease. Other disorders thatmay benefit from the activation of ceramidase include neurodegenerativedisorders such as Alzheimer's disease and amyotrophic lateral sclerosisand disorders of aging such as immune dysfunction, as well as disorders,such as those listed above, linked to elevated ceramide levels.

The compounds, salts, prodrugs, N-oxides, solvates and hydratesdescribed herein can be administered, for example, to a mammalian hostto retard cellular responses associated with the activation of theceramide-mediated signal transduction pathway. The compounds can beuseful, for example, in providing protection against cell senescence orapoptosis, such as occurs as a result of trauma (for example, radiationdermatitis) and aging (for example, of the skin or other organs).

Another embodiment is a method for up-regulating ceramidase function ina cell (either in vivo or in vitro), the method including contacting thecell with an effective amount of a compound, pharmaceutically acceptablesalt, prodrug, N-oxide (or solvate or hydrate thereof) or composition ofsuch a compound described above, such as a compound of one of formulas(I)-(LXXXVI).

In another embodiment, a method for decreasing ceramide concentration ina cell (either in vivo or in vitro) includes contacting the cell with aneffective amount of a compound, pharmaceutically acceptable salt,prodrug, N-oxide (or solvate or hydrate thereof) or composition of sucha compound described above, such as a compound of one of formulas(I)-(LXXXVI).

In another embodiment, a method for inhibiting ceramide-activatedresponses to stimuli in a cell (either in vivo or in vitro) includescontacting the cell with an effective amount of a compound,pharmaceutically acceptable salt, prodrug, N-oxide (or solvate orhydrate thereof) or composition described above. The stimuli can be, forexample, stimuli for cell senescence and/or apoptosis.

Another embodiment is a method for treating or preventing a disease ordisorder in which cell proliferation is deficient or desired in asubject, the method including administering to the subject an effectiveamount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide(or solvate or hydrate thereof) or composition of such a compounddescribed above, for example, a compound of one of formulas(I)-(LXXXVI). Various applicable diseases and disorders are describedabove.

Another embodiment is a method for treating a disease or disorder linkedto elevated ceramide levels in a subject, the method includingadministering to the subject an effective amount of a compound,pharmaceutically acceptable salt, prodrug, N-oxide (or solvate orhydrate thereof) or composition as described herein. Various applicablediseases and disorders are described above. In certain embodiments, thesubject has a ceramide level higher than about 50 pmol/10⁶ cells.

Moreover, since some drugs can induce high levels of ceramide, thecompounds, salts, prodrugs, N-oxides, solvates and hydrates describedherein can be usefully co-administered with such drugs in order to atleast partially ameliorate this effect. For example, in certainembodiments, an effective amount of a compound, pharmaceuticallyacceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) orcomposition as described herein is co-administered with a corticosteroid(for example, dexamethasone), an anti-inflammatory (for example,indomethacin), an antiviral (for example, interfereon), animmunosuppressant (for example, cyclosporin), a chemotherapy agent (forexample, adriamicin), and immunopotentiant (for example, animmunoglobulin or a vaccine), or an andocrinological agent (for example,metimazole). As the person of skill in the art will appreciate,co-administration contemplates not only administration at the same time,but also administration at different times, but with time-overlappingpharmacological effects.

Another embodiment is a method for reducing the effect of aging in theskin of a subject, the method including contacting the skin with acompound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvateor hydrate thereof) or composition as described herein.

Another embodiment is a method for treating or preventing radiationdermatitis in the skin of a subject, the method including contacting theskin with a compound, pharmaceutically acceptable salt, prodrug, N-oxide(or solvate or hydrate thereof) or composition as described herein.

To identify and select therapeutic compounds for use in treatingceramide-associated conditions, cells (or intracellular components suchas microsomes) which have not been exposed to a senescence orapoptosis-inducing agent (for example, cytokines such as TNF-α orexogenous stimuli such as heat, radiation or chemical agents) areexposed to such and agent and to the candidate compound. Inhibition ofsenescence or apoptosis is measured as a function of cell growth. Theperson of ordinary skill in the art will be familiar with techniques forobtaining such measurements.

For example, inhibition of cell senescence can be measured after serumdeprivation in serum-dependent cells. Many cell types are dependent uponserum factors for growth. Thus, deprivation of such cells of serumprovides a model for assessment of compounds to modulate cell responsesto intracellular ceramide-mediated signal transduction. In particular,withdrawal of serum from serum-dependent cell cultures producesincreased intracellular levels of endogenous ceramide and may alsoincrease intracellular levels of endogenous diacyl glycerol (see, e.g.,Jayadev, et al., J. Biol. Chem., 270, 2047-2052 (1995)). To evaluate theinhibitory effect of the compounds described herein onceramide-associated conditions in vitro, the serum withdrawal model canbe used. Specifically, 3T3 fibroblast cells can be seeded in 96 wellmicrotiter plates in DMEM in the presence of 10% fetal bovine serum. Thecells are incubated to 90% confluence. The medium is removed, and thecells washed and reincubated in serum-free DMEM. A test compound at avariety of concentrations (for example, 0, 4, 40 or 400 μM) and cellpermeable ceramide (for example, 0, 5 or 10 μM) are added to the wells.After 24 hrs. incubation, 0.5 μCi of [³H] thymidine is added to eachwell for 2 hrs. DNA synthesis in the tested cell population is assessedby conventional techniques for detection of [³H] thymidineincorporation. The results of this assay can be used to establish thecell senescence inhibitory efficacy of the test compound.

Inhibition of cell apoptosis can be determined, for example, using CD95stimulation. Engagement of cell surface receptor CD95 (also known asFas/Apo-1 antigen) triggers cell apoptosis. DX2 is a functional anti-FAS(CD95) antibody which will, on binding of CD95, activate thesphingomyelinase catalysis of sphingomyelin hydrolysis and production ofceramide (see, with respect to DX2, Cifone, et al., J. Exp. Med., 177,1547-1552 (1993)). Thus, binding of CD95 is a model for conduction ofapoptosis via the sphingomyelin signal transduction pathway. To assessthe inhibitory effect of the compounds disclosed herein onceramide-mediated cell apoptosis, human T lymphoblasts (Jurkat) aresuspended at 2×10⁶ cells/mL in RPMI-1640 supplemented with insulin,transferrin, selenium and glutamine. After incubation for 2 hrs. at roomtemperature with a test compound, pentoxifylline or a control compound(Ro-1724), 25 ng/mL of anti-FAS antibody is added to each suspension.After another 2 hrs., cell apoptosis is measured as a function of thenumber of cells (counted by hemocytometer) that excluded the vital dyeerythrosin B. The results of the experiment can be used to establish theapoptosis inhibitory efficacy of the test compound.

To assess the inhibitory effect of the compounds disclosed herein ondeath of human lymphocytes, human peripheral blood lymphocytes areisolated from normal human blood and depleted of monocytes by adherenceto a plastic substrate. Lymphocytes are then cultured in RPMI-1640medium with 10% autologous plasma at an initial concentration of 2×10⁶cells/mL. Aliquots of the cell samples are divided and one half of thesamples are incubated with a test compound or6,7-dimethoxy-1(2H)-isoquinoline (Aldrich) for four days. The remaininghalf of the samples are allowed to rest for four days. Cell viabilityafter four days is determined by erythrosin B dye exclusion in ahemocytometer. The results of the experiment can be used to establishthe apoptosis inhibitory efficacy of the test compound on humanlymphocytes as compared to untreated lymphocytes.

Ceramide-activated protein kinase (CaPK) is a 97 kDa protein which isexclusively membrane-bound and is believed to serve a role in thesphingomyelin signal transduction pathway. In particular, CaPK isbelieved to mediate phosphorylation of a peptide derived from the aminoacid sequence surrounding Thr.sup.669 of the epidermal growth factorreceptor (i.e., amino acids 663-681). This site is also recognized bythe mitogen-activated kinase MAP (also known as a family ofextracellular signal-regulated kinases). Thus, the effect of thecompounds disclosed herein on CaPK activity in cells can be indicativeof the effect that the compounds exert on signal transduction in thesphingomyelin pathway. Accordingly, Jurkat cells are suspended at 2×10⁶cells/mL in RPMI-1640 medium as described above with respect to the cellapoptosis experiment. After incubation for 2 hrs., either a testcompound; 20 μM of ceramide or 25 ng/ml of anti-FAS antibody DX2 areadded to each suspension and incubated for 15 mins. After centrifugationand washing, the cells were separately homogenized in a douncehomogenizer. Ceramide kinase levels in each test sample can be assayedas described by Liu, et al., J. Biol. Chem., 269, 3047-3052 (1994),which is hereby incorporated by reference herein in its entirety.Briefly, the membrane fraction is isolated from each test sample oftreated cell homogenate by ultracentrifugation and run on a 10% PAGEgel. The gel is washed with guanadine-HCl, and renatured in HEPESbuffer. Then [³²P]-ATP is added to the gel and left there for 10 mins.Thereafter, the gel is extensively washed with 5% TCA.Autophosphorylated kinase is detected by autoradiography. The results ofthis assay can be used to establish the CaPK inhibitory efficacy of thecompounds disclosed herein.

Ceramidase activity can be measured in a variety of ways. For example, asample from a subject or a sample of cells can be assayed in vitro forRNA or protein levels, structure, and/or activity of the expressedceramidase RNA or protein. Many methods standard in the art can be thusemployed, including but not limited to ceramidase enzyme assays.

Cellular ceramide levels can be monitored directly, or by indirectlymonitoring the concentrations of a ceramide metabolite in a cell. Forexample, ceramide levels can be directly measured by isolatingperipheral blood lymphocytes from a subject. The cells are centrifugedto remove supernatant, and lipids are removed from the cell pellet. Theorganic phase containing the ceramide can be assayed using thediacylglycerase kinase assay for phosphorylating the ceramide which isthen evidenced by autoradiography. Methods for performingdiacylglycerase kinase assays are described, for example, in Cifone, M.G. et al., J. Exp. Med., 180(4), 1547-52 (1993), Jayadev et al., J.Biol. Chem., 270, 2047-2052. (1995), and Perry, D. K. et al, MethodsEnzymology, 312, 22-31 (2000), each of which is hereby incorporated byreference in its entirety.

The presently disclosed AMPK activating compounds are useful forincreasing metabolic efficiency, for example by increasing fiberoxidative capacity, endurance and aerobic workload. In particular, thepresent compounds are useful for treating and regulating disorders ofmitochondrial function, including, without limitation, exerciseintolerance, chronic fatigue syndrome, muscle weakness, myoclonus,myoclonus epilepsy, such as associated with ragged-red fibers syndrome,Kearns-Sayre syndrome, Leigh's syndrome, mitochondrial myopathyencephalopathy lactacidosis stroke (MELAS) syndrome and stroke likeepisodes. The disclosed compounds also are useful for treating musculardystrophic states, such as Duchenne's and Becker's muscular dystrophiesand Friedreich's ataxia.

The presently disclosed AMPK activating compounds also function toreduce oxidative stress and secondary effects of such stress. Manydiseases, including several of those listed above, have secondaryeffects caused by damage due to excessive oxidative stress which can betreated using the compounds disclosed herein. For example, free radicaldamage has been implicated in neurological disorders, such asParkinson's disease, amyotrophic lateral sclerosis (Lou Gehrig'sdisease) and Alzheimers disease. Additional diseases in which excessivefree radical damage occurs generally include hypoxic conditions and avariety of other disorders. More specifically, such disorders includeischemia, ischemic reperfusion injury (such as coronary or cerebralreperfusion injury), myocardial ischemia or infarction, cerebrovascularaccidents (such as a thromboembolic or hemorrhagic stroke) that can leadto ischemia in the brain, operative ischemia, traumatic hemorrhage (forexample, a hypovolemic stroke that can lead to CNS hypoxia or anoxia),resuscitation injury, spinal cord trauma, inflammatory diseases,autoimmune disorders (such as rheumatoid arthritis or systemic lupuserythematosis), Down's syndrome, Hallervorden-Spatz disease, Huntingtonschorea, Wilson's disease, diabetic angiopathy (such as peripheralvascular disease or retinal degeneration), uveitis, chronic obstructivepulmonary disease (COPD), including chronic bronchitis and emphysema,asthma, neoplasia, Crohn's disease, inflammatory bowel disease andpancreatitis. Free radical damage is also implicated in a variety ofage-related disorders, particularly ophthalmic conditions such ascataracts and age-related macular degeneration.

In particular the present compounds are useful for treating neurologicaldisorders associated with reduced mitochondrial function, oxidativestress, or both. For example, Alzheimer's disease, dementia andParkinson's disease can be treated using the present AMPK activatingcompounds.

Metabolic efficiency is enhanced by the disclosed AMPK activatingcompounds. Thus the compounds can be administered to a subject toimprove exercise efficiency and athletic performance. Moreover,conditions including, without limitation, hypoxic states, anginapectoris, coronary ischemia and organ damage secondary to coronaryvessel occlusion, intermittent claudication, multi-infarct dementia,myocardial infarction, stroke, high altitude sickness and heart failure,including congestive heart failure can be treated using the disclosedcompounds.

Inflammatory disorders and effects can be treated using the presentcompounds. For example, in one aspect, the present compounds areparticularly useful for treating lung inflammation, such as is involvedin asthma, COPD and transplant rejection. Similarly, the presentcompounds are useful in reducing organ inflammation, particularlymacrophage-associated inflammation, such as inflammation of the kidney,liver and other organs. The anti-inflammatory activity of the presentlydisclosed compounds can be assessed as is known to those of skill in theart, for example, by using the mixed lymphocyte response in vitro.

Accordingly, one aspect of the disclosure relates to a method fortreating or ameliorating a disorder or condition related to oxidativestress, mitochondrial dysfunction, free radical damage and/or metabolicinefficiency in a subject in need thereof, the method includingadministering to the subject an effective amount of a compound,pharmaceutically acceptable salt, prodrug, N-oxide (or solvate orhydrate thereof) or pharmaceutical composition described above.

Another aspect of the present disclosure relates to a method for thetreatment or amelioration of a disorder of mitochondrial dysfunction ina subject in need thereof, the method including administering to thesubject an effective amount of a compound, pharmaceutically acceptablesalt, prodrug, N-oxide (or solvate or hydrate thereof) or pharmaceuticalcomposition described above. In certain embodiments, the disorder isselected from the group consisting of exercise intolerance, chronicfatigue syndrome, muscle weakness, myoclonus, myoclonus epilepsy (suchas associated with ragged-red fibers syndrome), Kearns-Sayre syndrome,Leigh's syndrome, mitochondrial myopathy encephalopathy lactacidosisstroke (MELAS) syndrome and stroke like episodes.

Another aspect of the disclosure relates to a method of increasingmetabolic efficiency in a subject in need thereof, the method includingadministering to the subject an effective amount of a compound,pharmaceutically acceptable salt, prodrug, N-oxide (or solvate orhydrate thereof) or pharmaceutical composition described above. Suchmethods can be used to increase fiber oxidative capacity, endurance,aerobic workload, or any combination thereof. These methods can be used,for example, to improve exercise efficiency, exercise endurance and/orathletic performance in a subject.

Another aspect of the present disclosure relates to methods formimicking the effects of exercise in a subject in need thereof, themethod including administering to the subject an effective amount of acompound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvateor hydrate thereof) or pharmaceutical composition described above.

Another aspect of the disclosure relates to a method for treating orameliorating a disorder in a subject in need thereof, the disorder beingselected from the group consisting of hypoxic states, angina pectoris,coronary ischemia and organ damage secondary to coronary vesselocclusion, intermittent claudication, multi-infarct dementia, myocardialinfarction, stroke, high altitude sickness and heart failure, includingcongestive heart failure, the method including administering to thesubject an effective amount of a compound, pharmaceutically acceptablesalt, prodrug, N-oxide (or solvate or hydrate thereof) or pharmaceuticalcomposition described above.

Another aspect of the disclosure relates to a method for the treatmentof amelioration of a muscular dystrophic state in a subject in needthereof, the method including administering to the subject an effectiveamount of a compound, pharmaceutically acceptable salt, prodrug, N-oxide(or solvate or hydrate thereof) or pharmaceutical composition describedabove. In certain embodiments, the muscular dystrophic state isDuchenne's muscular dystrophy, Becker's muscular dystrophy, orFreidreich's ataxia.

Another aspect of the disclosure relates to a method for increasingoxidative capacity of a muscle fiber, the method including contactingthe muscle fiber with a compound, pharmaceutically acceptable salt,prodrug, N-oxide (or solvate or hydrate thereof) or pharmaceuticalcomposition described above. The contacting may be performed in vitro orin vivo.

Another aspect of the disclosure relates to a method for reducingoxidative stress in a subject in need thereof, the method includingadministering to the subject an effective amount of a compound,pharmaceutically acceptable salt, prodrug, N-oxide (or solvate orhydrate thereof) or pharmaceutical composition described above.

Another aspect of the disclosure relates to a method for reducing freeradical damage in a subject in need thereof, the method includingadministering to the subject an effective amount of a compound,pharmaceutically acceptable salt, prodrug, N-oxide (or solvate orhydrate thereof) or pharmaceutical composition described above.

Another aspect of the disclosure relates to a method for treating orameliorating a disorder or condition in a subject in need thereof, thedisorder or condition selected from the group consisting of neurologicaldisorders, hypoxic conditions, ischemia, ischemic reperfusion injury,myocardial ischemia or infarction, cerebrovascular accidents, operativeischemia, traumatic hemorrhage, resuscitation injury, spinal cordtrauma, inflammatory diseases, autoimmune disorders, Down's syndrome,Hallervorden-Spatz disease, Huntingtons chorea, Wilson's disease,diabetic angiopathy, uveitis, chronic obstructive pulmonary disease(COPD), asthma, neoplasia, Crohn's disease, inflammatory bowel disease,pancreatitis and age-related disorders, the method includingadministering to the subject an effective amount of a compound,pharmaceutically acceptable salt, prodrug, N-oxide (or solvate orhydrate thereof) or pharmaceutical composition described above.Particular examples of such disorders and conditions are discussedabove.

Another aspect of the disclosure is a method for treating orameliorating a neurological disorder in a subject in need thereof, theneurological disorder being associated with reduced mitochondrialfunction, oxidative stress, or both, the method including administeringto the subject an effective amount of a compound, pharmaceuticallyacceptable salt, prodrug, N-oxide (or solvate or hydrate thereof) orpharmaceutical composition described above. Particular examples of suchneurological disorders are discussed above.

Another aspect of the disclosure relates to a method for reducingoxidative stress in a cell, the method including contacting the cellwith a compound, pharmaceutically acceptable salt, prodrug, N-oxide (orsolvate or hydrate thereof) or pharmaceutical composition describedabove. The contacting may be performed in vitro or in vivo.

Another aspect of the disclosure relates to a method for reducing freeradical damage in a cell, the method including contacting the cell witha compound, pharmaceutically acceptable salt, prodrug, N-oxide (orsolvate or hydrate thereof) or pharmaceutical composition describedabove. The contacting may be performed in vitro or in vivo.

Another aspect of the disclosure is a method for treating aninflammatory disorder or effect in a subject in need thereof, the methodincluding administering to the subject an effective amount of acompound, pharmaceutically acceptable salt, prodrug, N-oxide (or solvateor hydrate thereof) or pharmaceutical composition described above. Forexample, in one embodiment, the inflammatory disorder or effect is lunginflammation, such as is involved in asthma, COPD and transplantrejection. In another embodiment, the inflammatory disorder or effect isorgan inflammation, particularly macrophage-associated inflammation,such as inflammation of the kidney, liver and other organs.

Another embodiment is the use of a compound, pharmaceutically acceptablesalt, prodrug, N-oxide (or solvate or hydrate thereof) or composition asdescribed above in the manufacture of a medicament for any of thetherapeutic purposes described above. For example, the medicament can befor the reduction of triglyceride levels in a subject, the treatment oftype II diabetes in a subject, or the treatment or prevention ofatherosclerosis or cardiovascular disease in a subject. In otherembodiments, the medicament can be used to reduce the levels of cellularceramide in a subject, for example in the treatment of Batten's disease.

The compounds disclosed herein can be linked to labeling agents, forexample for use in variety of experiments exploring their receptorbinding, efficacy and metabolism. Accordingly, another embodiment is alabeled conjugate comprising a compound as disclosed herein covalentlylinked to a labeling agent, optionally through a linker. Suitable linkerand labeling agents will be readily apparent to those of skill in theart upon consideration of the present disclosure. The labeling agent canbe, for example, an affinity label such as biotin or strepavidin, ahapten such as digoxigenin, an enzyme such as a peroxidase, or afluorophoric or chromophoric tag. Any suitable linker can be used. Forexample, in some embodiments, an ethylene glycol, oligo(ethylene glycol)or poly(ethylene glycol) linker is used. Other examples of linkersinclude amino acids, which can be used alone or in combination withother linker groups, such as ethylene glycol, oligoethylene glycol orpolyethylene glycol. Suitable linkers include, without limitation,single amino acids, as well as di- and tripeptides.

In one embodiment, the linker includes a glycine residue. The person ofskill in the art will realize, of course, that other linkers andlabeling agents can be used. In other embodiments, an alkylene chain isthe linker. In other embodiments, the linker has the structure —[(C₀-C₃alkyl)-Y^(m)]_(m), in which each Y^(m) is —O—, —N(R⁹)—, or L, and m isin the range of 1-40. For example, in certain embodiments, a labeledconjugate has structural formula (LXXXVII):

in which the “LINK” moiety is a linker and is optional, and the “LABEL”moiety is a labeling agent, the LINK)₀₋₁-LABEL moiety is bound to thebracketed compound at any aryl or heteroaryl carbon (for example, of thecentral pyridine, pyridazine, pyrimidine or pyrazine, of the E moiety(e.g., of an R¹⁷ group thereof as in compound 403), or of the T moiety(e.g., of an “A” ring thereof as in compounds 371 and 394)). and allother variables are as described above, for example with reference tostructural formula (I). Any of the compounds disclosed with reference tostructural formulae (I)-(LXXXVI) can be used in the labeled conjugate ofstructural formula (LXXXVII).

For example, in one particular embodiment, a labeled conjugate hasstructural formula (LXXXVIII):

in which all variables are as described above, for example withreference to any of structural formulae (I)-(LXXXVI). The bond to thebracketed compound can be made, for example, at the central pyridine,pyridazine, pyrimidine or pyrazine.

Another disclosed embodiment of a labeled conjugate has the formula(LXXXIX):

The bond to the bracketed compound can be made, for example, at thecentral pyridine, pyridazine, pyrimidine or pyrazine.

Compounds of formulae (LXXXIX) can be synthesized by those of skill inthe art of organic synthesis, for example by reductive amination ofN-Boc-glycine aldehyde with a primary amine H₂NR², to yieldR²NHCH₂CH₂NHBoc, which is can be coupled to a pyridinecarboxylic acid tobuild up the target structure as described herein. The Boc protectinggroup can be removed, and the resulting amine further elaborated toprovide the labeled species.

In another particular embodiment, a labeled conjugate has structuralformula (XC):

in which all variables are as described above, for example withreference to any of structural formulae (I)-(LXXXVI). The bond to thebracketed compound can be made, for example, at the central pyridine,pyridazine, pyrimidine or pyrazine. Compound 159 is an example of anembodiment according to structural formula (XC).

Compounds according to structural formula (XC) can be made according toScheme 7, below, and as described with respect to Examples 159 and 164.

Referring to Scheme 7, a chloropyridinedicarboxylic acid monoethyl ester(xii) is coupled with an amine (here, a substituted 1-benzylpiperazine)to form a carboxymethyl-substituted chloropyridinecarboxamide (xiii),which is coupled with a protected propargyl amine to form acarboxyethyl-substituted alkynylpyridinecarboxamide (xiv). Compound(xiv) is saponified, then coupled with an amine (here, a substituted1-benzylpiperidine), to form a (3-amino-1-propyne)-substitutedpyridinedicarboxamide, Compound 164 of Table 1. Compound 164 isdeprotected, and the free amine is coupled with a biotinyl-linked acidto form Compound 159 of Table 1.

The following Examples are intended to further illustrate certainembodiments and are not intended to limit the scope of the disclosure.

EXAMPLES Example 1

The following compounds were made using methods analogous to those ofSchemes 1-7; in certain cases, exemplary synthetic procedures areprovided.

Compound 1N-(4-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(4-fluorobenzyl)piperizine-1-carbonyl)picolinamide.¹H nmr (CD₃OD) δ 8.96 (1H, s), 8.29 (1H, dd, J 8.0, 2.0 Hz), 7.71-7.64(3H, m), 7.55 (2H, d, J 8.0 Hz), 7.38-7.32 (2H, m), 7.04 (2H, t, J 8.5Hz), 3.96-3.85 (1H, m), 3.82-3.76 (2H, m), 3.62 (2H, s), 3.54 (2H, s),3.48-3.43 (2H, m), 2.91 (2H, m), 2.56 (2H, m), 2.45 (2H, m), 2.19 (2H,m), 1.95 (2H, m), 1.74-1.63 (3H, m); m/z: 542 [M+H]⁺.

Compound 2:N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(piperazine-1-carbonyl)picolinamide.¹H nmr (CD₃OD) δ 8.67 (1H, s), 8.15 (1H, d, J 8.0 Hz), 7.99 (1H, dd, J8.0, 2.0), 7.68 (2H, d, J 8.0 Hz), 7.54 (2H, d, J 8.0 Hz), 3.97-3.87(1H, m), 3.75 (2H, m), 3.62 (2H, s), 3.39 (2H, m), 2.97-2.74 (6H, m),2.23 (2H, m), 1.96-1.91 (2H, m), 1.80-1.66 (3H, m); m/z: 533 [M+H]⁺.

Compound 3:pyridine-2,5-diylbis((4-(4-fluorobenzyl)piperazin-1-yl)methanone). ¹Hnmr (CD₃OD) δ 8.62 (1H, s), 7.97 (1H, dd, J 8.0, 2.0 Hz), 7.66 (1H, d, J8.0 Hz), 7.38-7.32 (m, 4H), 7.07-7.01 (4H, m), 3.82-3.74 (4H, m),3.55-3.47 (8H, m), 2.58-2.54 (4H, m), 2.46-2.41 (4H, m); m/z: 520[M+H]⁺.

Compound 4:N-(1-(4-cyanobenzoyl)piperidin-4-yl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide.¹H nmr (CD₃OD) δ 8.66 (1H, s), 8.15 (1H, d, J 8.0 Hz), 7.99 (1H, dd, J8.0, 2.0 Hz), 7.84 (2H, d, J 8.5 Hz), 7.60 (2H, d, J 8.5 Hz), 7.37-7.32(2H, m), 7.04 (2H, t, J 9.0 Hz), 4.63 (1H, m), 4.24-4.17 (1H, m), 3.79(2H, m), 3.67-3.52 (4H, m), 3.43 (2H, m), 3.11-3.03 (1H, m), 2.56 (2H,m), 2.43 (2H, m), 2.14-1.85 (2H, m), 1.79-1.62 (2H, m); m/z: 555 [M+H]⁺.

Compound 5:N²-(1-(4-cyanobenzyl)piperidin-4-yl)-N⁵-(3-benzylphenyl)pyridine-2,5-dicarboxamide.¹H nmr (CDCl₃) δ 9.01 (1H, s), 8.26 (2H, s), 7.96 (1H, d, J 8.0 Hz),7.87 (1H, s), 7.61 (2H, d, J 8.5 Hz), 7.57 (2H, d, J 8.0 Hz), 7.45 (2H,d, J 8.0 Hz), 7.32-7.16 (m, 7H), 3.99 (3H, s), 3.56 (2H, s), 2.84 (2H,m), 2.22 (2H, m), 2.02 (2H, m), 1.72-1.61 (2H, m); m/z: 530 [M+H]⁺.

Compound 6:N-(4-((4-cyanophenyl)sulfonyl)piperidin-4-yl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 8.57 (1H, br s), 8.17 (1H, m), 7.91-7.83 (m, 6H), 7.28(1H, m), 7.01 (2H, m), 3.98-3.77 (5H, m), 3.57-3.30 (4H, m), 2.62-2.31(6H, m), 2.09 (2H, m), 1.78-1.62 (2H, m); m/z: 591 [M+H]⁺.

Compound 7:N-(1-(cyclohexanecarbonyl)piperidin-4-yl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide.m/z: 537 [M+H]⁺.

Compound 8:N-(1-(benzoyl)piperidin-4-yl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide.¹H nmr (CD₃OD) δ 8.66 (1H, m), 8.15 (1H, d, J 8.0 Hz), 7.98 (1H, dd, J8.0, 2.0), 7.48-7.40 (5H, m), 7.37-7.31 (2H, m), 7.07-7.01 (2H, m), 4.62(1H, m), 4.24-4.14 (1H, m), 3.78 (3H, m), 3.54 (2H, s), 3.43 (2H, m),3.26-3.00 (3H, m), 2.54 (2H, m), 2.42 (m, 2H), 2.10-1.84 (2H, m), 1.69(2H, m); m/z: 530 [M+H]⁺.

Compound 9:N-(1-(4-cyanobenzyl)-1H-pyrazol-3-yl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide.¹H nmr (CD₃OD) δ 8.68 (1H, m), 8.23 (1H, d, J 8.0 Hz), 8.02 (1H, dd, J8.0, 2.0 Hz), 7.71-7.64 (3H, m), 7.38-7.30 (4H, m), 7.02 (2H, m), 6.80(1H, m), 5.36 (2H, s), 3.76 (2H, m), 3.52 (2H, s), 3.43 (2H, m), 2.53(2H, m), 2.41 (2H, m); m/z: 524 [M+H]⁺.

Compound 10:N-(4-benzylphenyl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 9.88 (1H, s), 8.64 (1H, s), 8.32 (1H, d, J 8.0 Hz),7.92 (1H, dd, J 8.0, 2.0 Hz), 7.69 (2H, d, J 8.5 Hz), 7.33-7.17 (9H, m),7.02 (2H, m), 3.98 (2H, s), 3.83 (2H, s), 3.55-3.40 (4H, m), 2.62-2.36(4H, m); m/z: 510 [M+H]⁺.

Compound 11:5-(4-(4-fluorobenzyl)piperazine-1-carbonyl-N-(4-phenylphenyl)picolinamide.¹H nmr (D₆-DMSO) δ 10.79 (1H, s), 8.73 (1H, m), 8.20 (1H, d, J 8.0 Hz),8.06 (1H, dd, J 8.0, 2.0), 8.00 (2H, d, J 9.0 Hz), 7.67 (4H, m), 7.44(2H, t, J 8.0 Hz), 7.35-7.29 (3H, m), 7.13 (2H, t, J 9.0 Hz), 3.66 (2H,m), 3.49 (2H, s), 3.33 (2H, m), 2.44 (2H, m), 2.35 (2H, m); m/z: 495[M+H]⁺.

Compound 12:5-(4-(4-fluorobenzyl)piperazine-1-carbonyl-N-(3-phenylphenyl)picolinamide.¹H nmr (CDCl₃) δ 9.95 (1H, s), 8.60 (1H, m), 8.28 (1H, d, J 8.0 Hz),7.96 (1H, m), 7.86 (1H, dd, J 8.0, 2.0 Hz), 7.70 (1H, m), 7.57 (2H, d, J7.0 Hz), 7.42-7.19 (7H, m), 6.95 (2H, m), 3.76 (2H, m), 3.46 (2H, s),3.37 (2H, m), 2.49 (2H, m), 2.36 (2H, m); m/z: 495 [M+H]⁺.

Compound 13:N-(1-(cyclohexylmethyl)piperidin-4-yl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 8.56 (1H, s), 8.18 (1H, d, J 8.0 Hz), 7.98 (1H, d, J8.0 Hz), 7.86 (1H, dd, J 8.0, 2.0 Hz), 7.29-7.24 (2H, m), 7.03-6.95 (2H,m), 4.07 (1H, m), 3.79 (2H, m), 3.50 (2H, s), 3.38 (2H, m), 3.20-3.10(2H, m), 2.97 (1H, d, J 5.0 Hz), 2.60-2.35 (8H, m), 2.16-2.06 (2H, m),1.95-1.60 (6H, m), 1.31-1.08 (4H, m), 1.01-0.86 (2H, m); m/z: 522[M+H]⁺.

Compound 14:5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(1-(phenyl)piperidin-4-yl)picolinamide.¹H nmr (D₆-DMSO) δ 8.73 (1H, d, J 9.0 Hz), 8.62 (1H, m), 8.06 (1H, d, J8.0 Hz), 7.98 (1H, dd, J 8.0, 2.0 Hz), 7.35-7.28 (2H, m), 7.21-7.08 (4H,m), 6.96-6.91 (2H, m), 6.73 (1H, m), 3.97 (1H, m), 3.72-3.58 (4H, m),3.47 (2H, s), 2.82-2.70 (2H, m), 2.41 (2H, m), 2.31 (2H, m), 1.88-1.74(4H, m); m/z: 503 [M+H]⁺.

Compound 15:4-((8-(5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinoyl)-2,8-diazaspiro[4.5]decan-2-yl)methyl)benzonitrile.¹H nmr (D₆-DMSO) δ 8.56 (1H, s), 7.91 (2H, d, J 8.5 Hz), 7.78 (2H, m),7.57 (1H, t, J 8.0 Hz), 7.49 (1H, m), 7.32 (2H, m), 7.13 (2H, m), 3.62(4H, m), 3.47 (4H, m), 3.40-3.20 (8H, m), 2.44-2.37 (6H, m), 1.58 (4H,m); m/z: 582 [M+H]⁺.

Compound 16:5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(4-phenoxyphenyl)picolinamide.¹H nmr (CDCl₃) δ 9.84 (1H, s), 8.58 (1H, m), 8.26 (1H, d, J 8.0 Hz),7.85 (1H, dd, J 8.0, 2.0), 7.67 (2H, d, J 9.0 Hz), 7.30-7.18 (4H, m),7.06-6.90 (7H, m), 3.76 (2H, m), 3.46 (2H, s), 3.37 (2H, m), 2.49 (2H,m), 2.35 (2H, m); m/z: 512 [M+H]⁺.

Compound 17:(4-(4-fluorobenzyl)piperazin-1-yl)(6-(4-(benzyloxy)phenyl)pyridin-3-yl)methanone.To a mixture of(4-(4-fluorobenzyl)piperazin-1-yl)(6-bromopyridin-3-yl)methanone (0.048g, 0.13 mmol, 1.0 eq), 4-benzyloxyphenylboronic acid (0.040 g, 0.18mmol, 1.4 eq), potassium phosphate (0.053 g, 0.25 mmol, 1.9 eq), S-Phos(0.006 g, 0.01 mmol, 0.1 eq), andtris(dibenzylideneacetone)dipalladium(0) (0.012 g, 0.01 mmol, 0.01 eq)was added 1-butanol-water (1.25 mL, 4:1). Following a 5 minute purge ofthe reaction mixture with argon, the reaction vessel was sealed andheated at 100° C. for 10 hours. The reaction mixture was filteredthrough Celite®, eluting with 5% MeOH—CH₂Cl₂ and purified by RP-HPLC toprovide Compound 17. ¹H nmr (D₆-DMSO) δ 8.61 (1H, s), 8.06 (2H, d, J 9.0Hz), 7.95 (1H, d, J 8.0 Hz), 7.83 (1H, dd, J 8.0, 2.0 Hz), 7.48-7.30(7H, m), 7.16-7.10 (4H, m), 5.16 (2H, s), 3.61 (2H, m), 3.48 (2H, s),3.37 (2H, m), 2.38 (4H, m); m/z: 483 [M+H]⁺.

Compound 18:5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(1-(1-phenylethyl)piperidin-4-yl)picolinamide.¹H nmr (CDCl₃) δ 8.50 (1H, s), 8.13 (1H, d, J 8.0 Hz), 7.88 (1H, d, J8.0 Hz), 7.78 (1H, dd, J 8.0, 2.0 Hz), 7.32-7.18 (7H, m), 6.94 (2H, m),3.98-3.86 (1H, m), 3.74 (2H, m), 3.44 (2H, s), 3.32 (2H, m), 3.14 (1H,m), 2.98-2.85 (1H, m), 2.47 (2H, m), 2.38-2.14 (4H, m), 1.98 (2H, m),1.86-1.62 (3H, m), 1.48 (4H, m); m/z: 531 [M+H]⁺.

Compound 19:5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(2-phenylphenyl)picolinamide.¹H nmr (CDCl₃) δ 10.15 (1H, s), 8.56 (1H, d, J 8.0 Hz), 8.35 (1H, m),8.22 (1H, d, J 8.0 Hz), 7.78 (1H, dd, J 8.0, 2.0 Hz), 7.46-7.34 (6H, m),7.29-7.13 (4H, m), 6.95 (2H, m), 3.73 (2H, m), 3.53-3.22 (4H, m), 2.47(2H, m), 2.32 (2H, m); m/z: 496 [M+H]⁺.

Compound 20:5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(4-(4-nitrophenyl)phenyl)picolinamide.¹H nmr (D₆-DMSO) δ 10.93 (1H, s), 8.74 (1H, m), 8.28 (2H, d, J 9.0 Hz),8.20 (1H, d, J 8.0 Hz), 8.11-8.05 (3H, m), 7.97 (2H, d, J 9.0 Hz), 7.82(2H, d, J 9.0 Hz), 7.35-7.30 (2H, m), 3.65 (2H, m), 3.49 (2H, s), 3.35(2H, m), 2.43 (2H, m), 2.35 (2H, m); m/z: 541 [M+H]⁺.

Compound 21:5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(3-phenoxyphenyl)picolinamide.¹H nmr (CDCl₃) δ 9.85 (1H, s), 8.56 (1H, m), 8.24 (1H, d, J 8.0 Hz),7.84 (1H, dd, J 8.0, 2.0 Hz), 7.47-7.40 (2H, m), 7.32-7.18 (5H, m),7.00-6.91 (5H, m), 6.77-6.71 (1H, m), 3.76 (2H, m), 3.46 (2H, s), 3.36(2H, m), 2.49 (2H, m), 2.36 (2H, m); m/z: 512 [M+H]⁺.

Compound 22:(6-(3-(benzyloxy)phenyl)pyridin-3-yl)(4-(4-fluorobenzyl)piperazin-1-yl)methanone.¹H nmr (CDCl₃) δ 8.72 (1H, br s), 7.84-7.74 (2H, m), 7.96 (1H, s), 7.58(1H, d, J 8.0 Hz), 7.48-7.25 (8H, m), 7.08-6.98 (3H, m), 5.16 (2H, s),3.80 (2H, m), 3.53 (4H, m), 2.50 (4H, m); m/z: 483 [M+H]⁺.

Compound 23:N-(1-(4-cyanobenzyl)-1H-pyrazol-4-yl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 9.71 (1H, s), 8.56 (1H, m), 8.20 (1H, d, J 8.0 Hz),8.12 (1H, s), 7.84 (1H, dd, J 8.0, 2.0 Hz), 7.60-7.54 (3H, m), 7.26-7.18(4H, m), 6.95 (2H, m), 5.29 (2H, s), 3.76 (2H, m), 3.46 (2H, s), 3.36(2H, m), 2.60-2.27 (4H, m); m/z: 425 [M+H]⁺.

Compound 24:N-(4-(4-cyanophenyl)phenyl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 10.04 (1H, s), 8.67 (1H, m), 8.36 (1H, d, J 8.0 Hz),7.97-7.88 (3H, m), 7.75-7.61 (6H, m), 7.29 (2H, m), 7.03 (2H, m), 3.84(2H, m), 3.60-3.34 (4H, m), 2.49 (4H, m); m/z: 521 [M+H]⁺.

Compound 25:5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(4-(4-trifluoromethylphenyl)phenyl)picolinamide.¹H nmr (CDCl₃) δ 10.02 (1H, s), 8.68 (1H, m), 8.37 (1H, d, J 8.0 Hz),7.95 (1H, d, J 9.0 Hz), 7.89 (2H, d, J 8.5 Hz), 7.71-7.61 (6H, m), 7.28(2H, m), 7.04 (2H, m), 3.84 (2H, m), 3.60-3.38 (4H, m), 2.56 (2H, m),2.43 (2H, m); m/z: 564 [M+H]⁺.

Compound 26:N-(4-benzoylphenyl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 10.15 (1H, s), 8.67 (1H, m), 8.35 (1H, d, J 8.0 Hz),7.95 (1H, dd, J 8.0, 2.0 Hz), 7.90 (4H, m), 7.79 (2H, d, J 7.5 Hz), 7.59(1H, m), 7.49 (2H, m), 7.29 (2H, m), 7.02 (2H, m), 3.83 (2H, m), 3.54(2H, s), 3.47 (2H, m), 2.56 (2H, m), 2.43 (2H, m); m/z: 524 [M+H]⁺.

Compound 27:N-(4-benzyloxyphenyl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 9.75 (1H, s), 8.58 (1H, s), 2.27 (1H, d, J 8.0 Hz),7.84 (1H, dd, J 8.0, 2.0 Hz), 7.62 (2H, d, J 9.0 Hz), 7.39-7.18 (7H, m),6.96-6.90 (4H, m), 5.01 (2H, s), 3.76 (2H, m), 3.52-3.28 (4H, m),2.60-2.24 (4H, m); m/z: 526 [M+H]⁺.

Compound 28:N-(4-bromophenyl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 9.93 (1H, s), 8.65 (1H, s), 8.33 (1H, d, J 8.0 Hz),7.93 (1H, dd, J 8.0, 2.0 Hz), 7.68 (2H, d, J 9.0 Hz), 7.50 (2H, d, J 9.0Hz), 7.28 (2H, m), 7.02 (2H, m), 3.82 (2H, m), 3.52 (2H, s), 3.42 (2H,m), 2.49 (4H, m); m/z: 497, 499 [M+H]⁺.

Compound 29:N-(4-(4-methoxyphenyl)phenyl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 9.96 (1H, s), 8.66 (1H, m), 8.36 (1H, d, J 8.0 Hz),7.93 (1H, dd, J 8.0, 2.0 Hz), 7.83 (2H, d, J 9.0 Hz), 7.60-7.51 (4H, m),7.29 (2H, m), 7.03 (2H, m), 6.97 (2H, d, J 9.0 Hz), 3.85 (5H, m),3.60-3.36 (4H, m), 2.50 (4H, m); m/z: 526 [M+H]⁺.

Compound 30:(6-(4-benzylphenylamino)pyridin-3-yl)(4-(4-fluorobenzyl)piperazin-1-yl)methanone.¹H nmr (CDCl₃) δ 8.26 (1H, s), 7.56 (1H, dd, J 9.0, 1.0), 7.32-7.15(10H, m), 7.06-6.97 (3H, m), 6.77 (1H, d, J 8.5 Hz), 3.96 (2H, s), 3.66(4H, m), 3.52 (2H, s), 2.47 (4H, m); m/z: 482 [M+H]⁺.

Compound 31:4-((2-(5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)pyridin-2-yl)-2,8-diazaspiro[4.5]decan-8-yl)methyl)benzonitrile.m/z: 554 [M+H]⁺.

Compound 32:N-(4-(3-cyanophenyl)phenyl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 10.04 (1H, s), 8.67 (1H, s), 8.35 (1H, d, J 8.0 Hz),7.95 (1H, dd, J 8.0, 2.0), 7.94-7.80 (3H, m), 7.63-7.52 (3H, m), 7.28(2H, m), 7.02 (2H, m), 3.83 (2H, m), 3.53 (2H, s), 3.44 (2H, m), 2.48(4H, m); m/z: 521 [M+H]⁺.

Compound 33:(6-(3-phenylphenylamino)pyridin-3-yl)(4-(4-fluorobenzyl)piperazin-1-yl)methanone.¹H nmr (CDCl₃) δ 8.23 (1H, s), 7.56-7.47 (4H, m), 7.39-7.18 (9H, m),6.93 (2H, t, J 9.0 Hz), 6.80 (1H, d, 8.5 Hz), 3.59 (4H, m), 3.43 (2H,s), 2.39 (4H, m)); m/z: 468 [M+H]⁺.

Compound 34:(4-(4-fluorobenzyl)piperazin-1-yl)(6-(4-phenoxyphenylamino)pyridin-3-yl)methanone.¹H nmr (CDCl₃) δ 8.26 (1H, s), 7.58 (1H, dd, J 9.0, 2.0 Hz), 7.35-7.25(6H, m), 7.12-6.97 (8H, m), 6.73 (1H, d, J 9.0 Hz), 3.66 (4H, m), 3.51(2H, s), 2.46 (4H, m); m/z: 483 [M+H]⁺.

Compound 35:(6-(4-(4-cyanobenzylcarbamoyl)phenyl)pyridin-3-yl)(4-(4-fluorobenzyl)piperazin-1-yl)methanone.¹H nmr (CDCl₃) δ 8.64 (1H, br s), 7.96 (2H, d, J 8.0 Hz), 7.83 (2H, d, J8.0 Hz), 7.75-7.68 (2H, m), 7.56 (2H, d, J 8.0 Hz), 7.40 (2H, d, J 8.0Hz), 7.26-7.19 (2H, m), 7.01-6.91 (3H, m), 4.65 (2H, d, J 6.0 Hz), 3.73(2H, m), 3.47 (4H, m), 2.42 (4H, m); m/z: 535 [M+H]⁺.

Compound 36:(6-(4-(cyanobenzyl)piperidin-4-ylamino)pyridin-3-yl)(4-(4-fluorobenzyl)piperazin-1-yl)methanone.¹H nmr (CD₃OD) δ 8.06 (1H, s), 7.68 (2H, dd, J 8.0, 2.0 Hz), 7.44 (1H,m), 7.36-7.32 (2H, m), 7.06-6.98 (2H, m), 6.49 (2H, d, J 9.0 Hz),3.68-3.56 (6H, m), 3.34 (2H, s), 2.84 (2H, m), 2.46 (4H, m), 2.20 (2H,m), 1.96 (2H, m), 1.60-1.47 (2H, m); m/z: 514 [M+H]⁺.

Compound 37:(6-(4-phenylphenylamino)pyridin-3-yl)(4-(4-fluorobenzyl)piperazin-1-yl)methanone.¹H nmr (CDCl₃) δ 8.31 (1H, d, J 2.0 Hz), 7.65-7.55 (5H, m), 7.46-7.40(4H, m), 7.36-7.25 (3H, m), 7.16 (1H, s), 7.01 (2H, t, J 9.0 Hz), 6.87(1H, d, J 9.0 Hz), 3.68 (4H, m), 3.52 (2H, s), 2.48 (4H, m); m/z: 467[M+H]⁺.

Compound 38:N⁵-(1-(4-cyanobenzyl)-1H-pyrazol-3-yl)-N²-(1-(4-cyanobenzyl)piperidin-4-yl)pyridine-2,5-dicarboxamide.¹H nmr (CDCl₃) δ 8.98 (1H, s), 8.57 (1H, s), 8.22 (2H, m), 7.92 (1H, m),7.59-7.54 (4H, m), 7.46 (2H, m), 7.39 (1H, d, J 2.0 Hz), 7.21-7.16 (2H,m), 6.86 (1H, d, J 1.5 Hz), 5.21 (2H, s), 3.96 (1H, m), 3.57 (2H, s),2.89-2.80 (2H, m), 2.23 (2H, m), 1.97 (2H, m), 1.67 (2H, m); m/z: 546[M+H]⁺.

Compound 39:5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(4-(1H-pyrrol-3-yl)phenyl)picolinamide.¹H nmr (CDCl₃) δ 9.85 (1H, s), 8.58 (1H, s), 8.31 (1H, m), 8.27 (1H, d,J 8.0 Hz), 7.85 (1H, d, J 8.0, 2.0 Hz), 7.68 (2H, d, J 9.0 Hz), 7.48(2H, d, J 9.0 Hz), 7.24-7.18 (2H, m), 7.02 (1H, m), 6.95 (2H, t, J 8.5Hz), 6.77 (1H, m), 6.47 (1H, m), 3.76 (2H, m), 3.46-3.32 (4H, m), 2.48(2H, m), 2.36 (2H, m); m/z: 485 [M+H]⁺.

Compound 40:5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(4-morpholinophenyl)picolinamide.¹H nmr (CDCl₃) δ 9.74 (1H, s), 8.57 (1H, s), 8.26 (1H, d, J 8.0 Hz),7.84 (1H, dd, J 2.0 Hz), 7.62 (2H, d, J 9.0 Hz), 7.22 (2H, m), 6.94 (2H,t, J 9.0 Hz), 6.88 (2H, d, J 9.0 Hz), 3.83-3.53 (6H, m), 3.45 (2H, s),3.36 (2H, m), 3.08 (4H, m), 2.48 (2H, m), 2.35 (2H, m); m/z: 505 [M+H]⁺.

Compound 41:5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)picolinamide.¹H nmr (CDCl₃) δ 9.74 (1H, s), 8.57 (1H, m), 8.25 (1H, d, J 8.0 Hz),7.84 (1H, dd, J 8.0, 2.0), 7.60 (2H, d, J 9.0 Hz), 7.24-7.18 (2H, m),6.97-6.87 (4H, m), 3.75 (2H, m), 3.45 (2H, s), 3.36 (2H, m), 3.19 (4H,m), 2.60 (4H, m), 2.48 (2H, m), 2.34 (5H, m); m/z: 518 [M+H]⁺.

Compound 42:(6-(3-(4-cyanobenzylcarbamoyl)phenyl)pyridin-3yl)(4-(4-fluorobenzyl)piperazin-1-yl)methanone.¹H nmr (CDCl₃) δ 8.64 (1H, br s), 8.40 (1H, s), 8.07 (1H, d, J 8.0 Hz),7.86 (1H, d, J 8.0 Hz), 7.77 (2H, m), 7.59-7.47 (3H, m), 7.41 (2H, d, J8.0 Hz), 7.24-7.17 (2H, m), 6.95 (2H, t, J 9.0 Hz), 6.88 (1H, m), 4.66(2H, d, J 6.0 Hz), 3.74 (2H, m), 3.45 (4H, m), 2.42 (4H, m); m/z: 535[M+H]⁺.

Compound 43:N⁵-(1-(4-cyanobenzyl)-1H-pyrazol-4-yl)-N²-(1-(4-cyanobenzyl)piperidin-4-yl)pyridine-2,5-dicarboxamide.¹H nmr (D₆-DMSO) δ 10.83 (1H, s), 9.08 (1H, s), 8.70 (1H, d, J 8.0 Hz),8.43 (1H, dd, J 8.0, 2.0 Hz), 8.25 (1H, s), 8.13 (1H, d, J 8.5 Hz), 7.79(4H, m), 7.67 (1H, s), 7.49 (2H, d, J 8.0 Hz), 7.33 (2H, d, J 8.0 Hz),5.45 (2H, s), 3.80 (1H, m), 3.55 (2H, s), 2.76 (2H, m), 2.07 (2H, m),1.71 (4H, m); m/z: 546 [M+H]⁺.

Compound 44:(6-(1-(4-fluorobenzyl)-1H-pyrazol-4-ylamino)pyridin-3-yl)(4-(4-fluorobenzyl)piperazin-1-yl)methanone.¹H nmr (CDCl₃) δ 8.15 (1H, d, J 2.0 Hz), 7.61 (1, 1H), 7.46 (1H, dd, J8.0, 2.0 Hz), 7.42 (1H, s), 7.24-7.12 (4H, m), 6.99-6.90 (4H, m), 6.70(1H, s), 6.45 (1H, d, J 8.5 Hz), 5.17 (2H, s), 3.57 (4H, m), 3.44 (2H,m), 2.39 (4H, m); m/z: 489 [M+H]⁺.

Compound 45:N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(1-(4-fluorobenzyl)-1H-pyrazol-4-ylamino)picolinamide.¹H nmr (CDCl₃) δ 7.92 (1H, d, J 3.0 Hz), 7.89 (1H, d, J 9.0 Hz), 7.62(1H, d, J 8.5 Hz), 7.54 (2H, d, J 8.0 Hz), 7.44-7.38 (3H, m), 7.30 (1H,s), 7.19-7.13 (2H, m), 7.02-6.94 (3H, m), 5.49 (1H, s), 5.19 (2H, s),3.98-3.84 (1H, m), 3.52 (2H, s), 2.76 (2H, m), 2.17 (2H, m), 1.93 (2H,m), 1.57 (2H, m); m/z: 511 [M+H]⁺.

Compound 46:(6-(1-(4-cyanobenzyl)piperidine-4-carboxamido)pyridin-3-yl)(4-(4-fluorobenzyl)piperazin-1-yl)methanone.To a mixture of(4-(4-fluorobenzyl)piperazin-1-yl)(6-bromopyridin-3-yl)methanone (0.040g, 0.11 mmol, 1.0 eq), 1-(4-cyanobenzyl)piperidine-4-carboxamide (0.028g, 0.12, 1.1 eq), and N,N′-dimethylethylenediamine (0.012 mL, 0.11 mmol,1.0 eq) was added anhydrous toluene (1.0 mL). This mixture was purgedwith argon for 5 minutes and copper(I)iodide (0.011 g, 0.058 mmol, 0.5eq) and potassium carbonate (0.044 g, 0.23 mmol, 2.1 eq) were added. Thereaction mixture was heated at 100° C. for 4.5 hours and then absorbedon silica gel. Purification by column chromatography (silica, 0→5%MeOH—CH₂Cl₂) yielded a green solid (0.070 g). Further purification usingpreparative TLC (silica, 4% MeOH—CH₂Cl₂) provided Compound 46 as a whitesolid (0.040 g, 67%). ¹H nmr (D₆-DMSO) δ 10.64 (1H, s), 8.32 (1H, s),8.10 (1H, d, J 8.5 Hz), 7.81-7.74 (3H, m), 7.53-7.46 (2H, m), 7.31 (2H,t, J 8.0 Hz), 7.12 (2H, t, J 9.0 Hz), 3.64-3.36 (9H, m), 2.79 (2H, m),2.35 (m, 4H), 1.99-1.87 (2H, m), 1.79-1.54 (4H, m); m/z: 542 [M+H]⁺.More information about this type of coupling is provided in Wrona, IwonaE.; Gozman, Alexander; Taldone, Tony; Chiosis, Gabriela; Panek, James S.Journal of Organic Chemistry (2010), 75(9), 2820-2835.

¹H nmr (D₆-DMSO) δ 10.64 (1H, s), 8.32 (1H, s), 8.10 (1H, d, J 8.5 Hz),7.81-7.74 (3H, m), 7.53-7.46 (2H, m), 7.31 (2H, t, J 8.0 Hz), 7.12 (2H,t, J 9.0 Hz), 3.64-3.36 (9H, m), 2.79 (2H, m), 2.35 (m, 4H), 1.99-1.87(2H, m), 1.79-1.54 (4H, m); m/z: 542 [M+H]⁺.

Compound 47:N-(4-(4-cyanobenzylcarbamoyl)phenyl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 10.03 (1H, s), 8.58 (1H, s), 8.24 (1H, d, J 8.0 Hz),7.84 (1H, dd, J 8.0, 2.0 Hz), 7.78 (4H, m), 7.57 (2H, d, J 8.0 Hz), 7.40(2H, d, J 8.0 Hz), 7.26-7.19 (2H, m), 6.95 (2H, t, J 9.0 Hz), 6.68 (1H,m) 4.64 (2H, d, J 6.0 Hz), 3.76 (2H, m), 3.47 (2H, s), 3.37 (2H, m),2.49 (2H, m), 2.36 (2H, m); m/z: 578 [M+H]⁺.

Compound 48:(6-(4-(4-cyanobenzylcarbamoyl)phenylamino)pyridin-3-yl)(4-(4-fluorobenzyl)piperazin-1-yl)methanone.¹H nmr (CDCl₃) δ 8.25 (1H, s), 7.81 (1H, s), 7.70 (1H, d, J 9.0 Hz),7.53-7.33 (8H, m), 7.28-7.23 (2H, m), 6.99 (2H, t, J 9.0 Hz), 6.73 (1H,d, J 8.5 Hz), 4.60 (2H, d, J 6.0 Hz), 3.60 (4H, m), 3.48 (2H, s), 2.43(4H, m); m/z: 550 [M+H]⁺.

Compound 49:N-(1-(3,5-difluorobenzyl)piperidin-4-yl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 8.52 (1H, s), 8.16 (1H, d, J 8.0 Hz), 7.86 (1H, d, J8.0 Hz), 7.81-7.78 (1H, m), 7.23-7.07 (3H, m), 7.06-6.91 (4H, m),4.20-3.88 (1H, m), 3.74 (2H, m), 3.44 (2H, s), 3.43 (2H, s), 3.33 (2H,m), 2.78 (2H, m), 2.47 (2H, m), 2.321 (2H, m), 2.16 (2H, m), 1.96 (2H,m), 1.62 (2H, m); m/z: 553 [M+H]⁺.

Compound 50:5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(1-(4-fluoro-3-methylbenzyl)piperidin-4-yl)picolinamide.¹H nmr (CDCl₃) δ 8.51 (s, 1H), 8.16 (1H, d, J 8.0 Hz), 7.85 (1H, d, J9.0 Hz), 7.79 (1H, d, J 8.0 Hz), 7.23-7.18 (2H, m), 7.10-7.01 (2H, m),6.97-6.84 (3H, m), 3.99-3.88 (1H, m), 3.74 (2H, m), 3.44 (2H, s), 3.40(2H, s), 3.33 (2H, m), 2.79 (2H, m), 2.47 (2H, m), 2.32 (2H, m), 2.20(3H, s), 2.13 (1H, m), 1.94 (2H, m), 1.60 (3H, m); m/z: 549 [M+H]⁺.

Compound 51:N-(1-(4-chlorobenzyl)piperidin-4-yl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide.¹H nmr (CD₃OD) δ 8.67 (1H, m, major isomer), 8.63 (1H, m, minor isomer),8.16 (1H, d, J 8.0 Hz), 8.00 (1H, dd, J 8.0, 2.0 Hz), 7.38-7.32 (2H, m),7.09-7.00 (5H, m), 6.81 (2H, d, J 9.0 Hz), 4.10 (m), 3.80 (m), 3.57 (s),3.45 (m), 3.30 (m), 2.96 (s), 2.58-2.44 (m), 1.94-1.60 (m), 1.39-1.28(m); m/z: 546 [M+H]⁺.

Compound 52:N-(1-(4-chlorobenzyl)piperidin-4-yl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 8.57 (1H, s), 8.21 (1H, d, J 8.0 Hz), 7.90 (1H, d, J8.0 Hz), 7.84 (1H, dd, J 8.0, 2.0), 7.28-7.22 (6H, m), 6.99 (2H, m),4.04-3.92 (1H, m), 3.79 (2H, m), 3.49 (2H, s), 3.46 (2H, s), 3.38 (2H,m), 2.81 (2H, m), 2.52 (2H, m), 2.37 (2H, m), 2.17 (2H, m), 1.98 (2H,m), 1.62 (2H, m); m/z: 551, 553 [M+H]⁺.

Compound 53:5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(4-(4-methylphenoxy)phenyl)picolinamide.¹H nmr (CDCl₃) δ 9.88 (1H, s), 8.64 (1H, s), 8.33 (1H, d, J 8.0 Hz),7.91 (1H, dd, J 8.0, 2.0 Hz), 7.71 (2H, d, J 9.0 Hz), 7.30-7.24 (2H, m),7.13 (2H, d, J 8.0 Hz), 7.03-6.96 (4H, m), 6.91 (2H, d, J 8.5 Hz), 3.82(2H, m), 3.51 (2H, s), 3.42 (2H, m), 2.54 (2H, m), 2.41 (2H, m), 2.33(3H, s); m/z: 526 [M+H]⁺.

Compound 54:5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(4-(4-methoxyphenoxy)phenyl)picolinamide.¹H nmr (CDCl₃) δ 9.87 (1H, m), 8.64 (1H, s), 8.32 (1H, d, J 8.0 Hz),7.91 (1H, dd, J 8.0, 2.0 Hz), 7.69 (2H, d, J 9.0 Hz), 7.30-7.24 (2H, m),7.03-6.95 (6H, m), 6.87 (2H, m), 3.80 (5H, m), 3.51 (2H, s), 3.42 (2H,m), 2.54 (2H, m), 2.41 (2H, m); m/z: 541 [M+H]⁺.

Compound 55:5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(4-(3-fluorophenoxy)phenyl)picolinamide.¹H nmr (CDCl₃) δ 9.86 (1H, s), 8.59 (1H, s), 8.26 (1H, d, J 8.0 Hz),7.85 (1H, dd, J 8.0, 2.0 Hz), 7.70 (2H, d, J 9.0 Hz), 7.24-7.15 (3H, m),7.00 (2H, d, J 9.0 Hz), 6.94 (2H, t, J 9.0 Hz), 6.74-6.60 (3H, m), 3.75(2H, m), 3.45 (2H, s), 3.36 (2H, m), 2.48 (2H, m), 2.34 (2H, m); m/z:530 [M+H]⁺.

Compound 56:N-(4-(3-cyanophenoxy)phenyl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 9.90 (1H, s), 8.59 (1H, s), 8.27 (1H, d, J 8.0 Hz),7.86 (1H, dd, J 8.0, 2.0 Hz), 7.74 (2H, d, J 9.0 Hz), 7.38-7.25 (2H, m),7.24-7.14 (4H, m), 7.00 (2H, d, J 9.0 Hz), 6.94 (2H, t, J 8.5 Hz), 3.76(2H, m), 3.45 (2H, s), 3.36 (2H, m), 2.48 (2H, m), 2.35 (2H, m); m/z:537 [M+H]⁺.

Compound 57:5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(4-(3-methoxyphenoxy)phenyl)picolinamide.¹H nmr (CDCl₃) δ 9.84 (1H, s), 8.59 (1H, s), 8.26 (1H, d, J 8.0 Hz),7.85 (1H, dd, J 8.0, 2.0 Hz), 7.67 (2H, d, J 9.0 Hz), 7.24-7.11 (3H, m),7.01-6.91 (4H, m), 6.60-6.48 (3H, m), 3.76 (2H, m), 3.70 (3H, s), 3.45(2H, s), 3.37 (2H, m), 2.48 (2H, m), 2.34 (2H, m); m/z: 542 [M+H]⁺.

Compound 58:5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(4-(3-methylphenoxy)phenyl)picolinamide.¹H nmr (CDCl₃) δ 9.90 (1H, s), 8.65 (1H, s), 8.33 (1H, d, J 8.0 Hz),7.92 (1H, dd, J 8.0, 2.0 Hz), 7.73 (2H, d, J 9.0 Hz), 7.31-7.25 (2H, m),7.21 (1H, t, J 7.5 Hz), 7.06-6.96 (4H, m), 6.90 (2H, d, J 7.5 Hz), 6.82(2H, m), 3.82 (2H, m), 3.51 (2H, s), 3.42 (2H, s), 2.54 (2H, m), 2.41(2H, m), 2.32 (3H, s); m/z: 526 [M+H]⁺.

Compound 59:N-(4-(4-cyanophenoxy)phenyl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 9.91 (1H, s), 8.59 (1H, s), 8.27 (1H, d, J 8.5 Hz),7.87 (1H, dd, J 8.0, 1.5 Hz), 7.76 (2H, d, J 9.0 Hz), 7.53 (2H, d, J 8.5Hz), 7.24-7.18 (2H, m), 7.04 (2H, d, J 9.0 Hz), 6.98-6.91 (4H, m), 3.76(2H, m), 3.45 (2H, s), 3.36 (2H, m), 2.49 (2H, m), 2.35 (2H, m); m/z:537 [M+H]⁺.

Compound 60:5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(4-(4-fluorophenoxy)phenyl)picolinamide.¹H nmr (CDCl₃) δ 9.84 (1H, s), 8.58 (1H, s), 8.27 (1H, d, J 8.5 Hz),7.88-7.84 (1H, m), 7.66 (2H, d, J 9.0 Hz), 7.24-7.18 (3H, m), 6.99-6.88(7H, m), 3.76 (2H, m), 3.45 (2H, s), 3.36 (2H, m), 2.48 (2H, m), 2.34(2H, m); m/z: 530 [M+H]⁺.

Compound 61:5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(4-(pyridine-3-yl)phenyl)picolinamide.¹H nmr (CDCl₃) δ 9.97 (1H, s), 8.80 (1H, s), 8.61 (1H, s), 8.51 (1H, d,J 5.0 Hz), 7.90-7.80 (4H, m), 7.56 (2H, d, J 8.5 Hz), 7.33-7.27 (1H, m),7.25-7.18 (2H, m), 6.95 (2H, t, J 8.5 Hz), 3.76 (2H, m), 3.45 (2H, s),3.37 (2H, m), 2.49 (2H, m), 2.35 (2H, m); m/z: 497 [M+H]⁺.

Compound 62:5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(4-(thiophen-3-yl)phenyl)picolinamide.¹H nmr (CDCl₃) δ 9.91 (1H, s), 8.59 (1H, m), 8.28 (1H, d, J 8.0 Hz),7.86 (1H, dd, J 8.0, 2.0 Hz), 7.75 (2H, d, J 8.5 Hz), 7.56 (2H, d, J 8.5Hz), 7.38-7.31 (2H, m), 7.24-7.16 (3H, m), 6.94 (2H, t, J 8.5 Hz), 3.76(2H, m), 3.45 (2H, s), 3.36 (2H, m), 2.48 (2H, m), 2.34 (2H, m); m/z:502 [M+H]⁺.

Compound 63:5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-(6-(4-cyanophenoxy)pyridin-3-yl)picolinamide.¹H nmr (CDCl₃) δ 9.89 (1H, s), 8.60 (1H, m), 8.40 (1H, d, J 2.5 Hz),8.35 (1H, dd, J 9.0, 3.0 Hz), 8.26 (1H, dd, J 8.5, 1.0 Hz), 7.88 (1H,dd, J 8.0, 2.0 Hz), 7.61 (2H, d, J 9.0 Hz), 7.25-7.13 (4H, m), 7.00 (1H,d, J 9.0 Hz), 6.94 (2H, t, J 8.5 Hz), 3.76 (2H, m), 3.45 (2H, s), 3.35(2H, m), 2.48 (2H, m), 2.35 (2H, m); m/z: 538 [M+H]⁺.

Compound 64:5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-(6-(3-cyanophenoxy)pyridin-3-yl)picolinamide.¹H nmr (CDCl₃) δ 9.87 (1H, s), 8.60 (1H, m), 8.36 (2H, m), 8.26 (1H, d,J 8.5 Hz), 7.87 (1H, dd, J 8.0, 2.0 Hz), 7.46-7.31 (3H, m), 7.23-7.18(3H, m), 7.02-6.90 (3H, m), 3.76 (2H, m), 3.45 (2H, s), 3.35 (2H, m),2.48 (2H, m), 2.35 (2H, m); m/z: 538 [M+H]⁺.

Compound 65:5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3-yl)picolinamide.¹H nmr (CDCl₃) δ 9.83 (1H, s), 8.58 (1H, m), 8.37-8.21 (4H, m), 7.86(1H, dd, J 8.0, 2.0 Hz), 7.24-7.17 (2H, m), 7.05-6.86 (6H, m), 3.75 (2H,m), 3.44 (2H, s), 3.34 (2H, m), 2.48 (2H, m), 2.34 (2H, m); m/z: 531[M+H]⁺.

Compound 66:5-(4-(4-cyano-2-methoxyphenoxy)piperidine-1-carbonyl)-N-(1-(4-cyanobenzyl)piperidin-4-yl)picolinamide.¹H nmr (CDCl₃) δ 8.54 (1H, m), 8.18 (1H, d, J 8.0 Hz), 7.87-7.80 (2H,m), 7.55 (2H, d, J 8.5 Hz), 7.39 (2H, d, J 8.0 Hz), 7.21-7.15 (1H, m),7.05 (1H, m), 6.87 (1H, d, J 8.0 Hz), 4.66-4.58 (1H, m), 3.97-3.78 (6H,m), 3.60 (1H, m), 3.50 (2H, s), 3.41 (2H, m), 3.31 (1H, m), 2.76 (2H,m), 2.16 (2H, m), 2.20-1.57 (4H, m), 1.63-1.52 (2H, m); m/z: 580 [M+H]⁺.

Compound 67:5-(4-(4-fluoro-4-fluorobenzoyl)piperidine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3-yl)picolinamide.¹H nmr (CDCl₃) δ 9.83 (1H, s), 8.64 (1H, s), 8.36-8.24 (3H, m),8.11-8.05 (2H, m), 7.92 (1H, dd, J 8.0, 2.0 Hz), 7.11-6.97 (6H, m), 6.89(1H, d, J 9.0 Hz), 4.62 (1H, m), 3.70-3.41 (3H, m), 2.36-1.91 (4H, m);m/z: 562 [M+H]⁺.

Compound 68:N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-fluoro-4-fluorobenzoyl)piperidine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 8.57 (1H, s), 8.19 (1H, d, J 8.0 Hz), 8.09-8.04 (2H,m), 7.88-7.82 (2H, m), 7.54 (2H, d, J 8.5 Hz), 7.39 (2H, d, J 8.0 Hz),7.08 (2H, t, J 8.5 Hz), 4.60 (1H, m), 3.99-3.90 (1H, m), 3.60-3.30 (4H,m), 2.75 (2H, m), 2.28-2.07 (6H, m), 1.95 (3H, m), 1.65-1.53 (2H, m);m/z: 573 [M+H]⁺.

Compound 69:5-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3-yl)picolinamide.¹H nmr (CDCl₃) δ 9.85 (1H, s), 8.62 (1H, s), 8.37-8.25 (3H, m),7.92-7.85 (3H, m), 7.06-6.99 (4H, m), 6.90 (3H, m), 4.62 (1H, m), 3.81(3H, s), 3.72 (1H, m), 3.49 (1H, s), 3.28-2.98 (2H, m), 1.97 (1H, m),1.77 (3H, m); m/z: 556 [M+H]⁺.

Compound 70:5-(4-(4-methoxyphenoxy)piperidine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3-yl)picolinamide.¹H nmr (CDCl₃) δ 9.84 (1H, s), 8.61 (1H, s), 8.35-8.25 (2H, m), 7.89(1H, dd, J 8.0, 2.0 Hz), 7.06-7.01 (4H, m), 6.90 (1H, d, J 9.0 Hz),6.83-6.75 (4H, m), 4.43 (1H, m), 3.84 (2H, m), 3.70 (3H, m), 3.31 (1H,m), 1.93 (2H, m), 1.79 (2H, m); m/z: 544 [M+H]⁺.

Compound 71:trans-N-(4-(4-cyanophenoxy)cyclohexyl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 8.53 (1H, s), 8.18 (1H, d, J 8.0 Hz), 7.86-7.80 (2H,m), 7.51 (2H, d, J 9.0 Hz), 7.00 (2H, t, J 8.5 Hz), 4.27 (1H, m),4.07-3.40 (7H, m), 2.65 (4H, m), 2.13 (4H, m), 1.68-1.57 (2H, m),1.49-1.38 (2H, m); m/z: 543 [M+H]⁺.

Compound 94:(4-(4-fluorobenzyl)piperazin-1-yl)(6-(4-phenylpiperazine-1-carbonyl)pyridin-2-yl)methanone.To a suspension of pyridine-2,6-dicarboxylic acid (0.200 g, 1.20 mmol,1.0 eq) in tetrahydrofuran (6.0 mL) was added 4-fluorobenzylpiperazine(0.116 g, 0.60 mmol, 0.5 eq). Triethylamine (0.33 mL, 2.40 mmol, 2.0 eq)was added followed by HATU (0.319 g, 0.84 mmol, 0.7 eq) and the reactionwas stirred at room temperature for 14 hours. The reaction mixture wasdiluted with methanol (3.0 mL) and (trimethylsilyl)diazomethane (2.0 mLof a 2M solution in hexane, 4.00 mmol). The reaction mixture was stirredat room temperature for 30 minutes before concentrating under reducedpressure. The residue was partitioned between NaHCO₃ (50 mL) and EtOAc(50 mL). The organics were washed with brine (50 mL), dried (Na₂SO₄) andconcentrated under reduced pressure. Column chromatography (silica, 2→5%MeOH—CH₂Cl₂) yielded methyl6-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinate (0.214 g, 50%) asa white solid; m/z: 358 [M+H]⁺. To a solution of the methyl6-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinate (0.214 g, 0.60mmol, 1.0 eq) in tetrahydrofuran (4.0 mL) was added a solution oflithium hydroxide monohydrate (0.050 g, 1.20 mmol, 2.0 eq) in water (3.0mL). The reaction was stirred at room temperature for 25 minutes beforeneutralizing with HCl (approximately 0.6 mL of a 2M solution). Thereaction mixture was concentrated to dryness to yield6-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinic acid, which wasused without further purification; m/z: 344 [M+H]⁺. To a solution of thecrude 6-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinic acid(approximately 0.200 mmol, 1.0 eq) and triethylamine (0.083 mL, 0.600mmol, 3.0 eq) in dimethylformamide (2.0 mL) was added 1-phenylpiperazine(0.036 mL, 0.240 mmol, 1.2 eq). HATU was added and the reaction shakenat room temperature for 2.5 hours before partitioning between EtOAc (50mL) and NaHCO₃-water (1:1, 50 mL). The organics were further washed withbrine (50 mL), water (50 mL) and brine (50 mL) before drying (Na₂SO₄)and concentrating under reduced pressure. Column chromatography (silica,3→7% MeOH—CH₂Cl₂) yielded Compound 94 as a colourless oil; ¹H nmr(CDCl₃) δ 7.92 (1H, t, J 7.5 Hz, pyH-4), 7.73 (1H, d, J 8.0 Hz, pyH-3 orpyH-5), 7.70 (1H, d, J 7.5 Hz, pyH-3 or pyH-5), 7.33-7.22 (4H, m, 2H ofC₆H₄F and 2H of C₆H₅), 7.01-6.90 (5H, m, 2H of C₆H₄F and 3H of C₆H₅),3.97 (2H, dd, J 5.5, 5.0 Hz, 2H of piz), 3.81 (2H, dd, J 5.0, 4.5 Hz, 2Hof piz), 3.74 (2H, t, J 5.0 Hz, 2H of piz), 3.55 (2H, dd, J 5.0, 4.5 Hz,2H of piz), 3.46 (2H, s, CH ₂C₆H₄F), 3.29 (2H, t, J 5.0 Hz, 2H of piz),3.17 (2H, dd, J 5.5, 4.5 Hz, 2H of piz), 2.52 (2H, t, J 5.0 Hz, 2H ofpiz), 2.39 (2H, dd, 5.0, 4.5 Hz, 2H of piz); m/z: 488 [M+H]⁺.

Compound 140:N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(3,5-difluorobenzyl)piperazine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 8.58 (1H, br s, pyH-6), 8.23 (1H, d, J 8.0 Hz, pyH-3),7.91 (1H, d, J 9.0 Hz, NH), 7.86 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.61(2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.45 (2H, d, J 8.0 Hz, 2H of C₆H₄CN),6.87 (2H, d, J 6.5 Hz, H-2 and H-6 of C₆H₃F₂), 6.70 (1H, t, J 9.0 Hz,H-4 of C₆H₃F₂), 4.00 (1H, m, pipH-4), 3.82 (2H, m, 2H of piz), 3.56 (2H,s, 1×CH₂Ar), 3.51 (2H, s, 1×CH₂Ar), 3.41 (2H, m, 2H of piz), 2.81 (2H,m, 2H of pip), 2.55 (2H, m, 2H of piz), 2.40 (2H, m, 2H of piz), 2.22(2H, t, J 11.0 Hz, 2H of pip), 2.01 (2H, m, 2H of pip), 1.64 (2H, m, 2Hof pip); m/z: 560 [M+H]⁺.

Compound 141:5-(4-(4-carbamoylbenzyl)piperidine-1-carbonyl)-N-(1-(4-cyanobenzyl)piperidin-4-yl)picolinamide.¹H nmr (D₆-DMSO) δ 8.65 (2H, m, NH, 1×pyH), 8.04 (1H, m, 2×pyH), 7.81(1H, d, J 8.5 Hz, 2H of C₆H₄CN or C₆H₄CONH₂), 7.78 (2H, d, J 8.0 Hz, 2Hof C₆H₄CN or C₆H₄CONH₂), 7.49 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.01 (2H,d, J 9.0 Hz, 2H of C₆H₄CONH₂), 4.75 (1H, m, oxypipH-4), 4.09 (1H, m, 1Hof oxypipH-2, H-6), 3.80 (1H, m, pipH-4), 3.54 (2H, s, CH₂C₆H₄CN), 3.48(2H, m, 2H of oxypipH-2, H-6), 3.25 (1H, m, 1H of oxypipH-2, H-6), 2.75(2H, m, 2H of pipH-2, H-6), 2.06 (3H, m, 2H of pipH-2, H-6, 1H ofoxypipH-3, H-5), 1.91 (1H, m, 1H of oxypipH-3, H-5), 1.71 (6H, m, 4H ofpipH-3, H-5, 2H of oxypipH-3, H-5); m/z: 568 [M+H]⁺.

Compound 142:N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-((4-fluorophenyl)(hydroxy)methyl)piperidine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 8.56 (1H, br s, pyH-6), 8.21 (1H, d, J 7.0 Hz, pyH-3),7.91 (1H, d, J 8.5 Hz, NH), 7.85 (1H, m, pyH-4), 7.61 (2H, d, J 8.0 Hz,2H of C₆H₄CN), 7.45 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.26 (2H, m, 2H ofC₆H₄F), 7.04 (2H, t, J 8.5 Hz, 2H of C₆H₄F), 4.75 (1H, m, 1H ofBnpipH-2, H-6), 4.43 (1H, d, J 7.0 Hz, CH(OH)C₆H₄F), 3.99 (1H, m,pipH-4), 3.66 (1H, m, 1H of BnpipH-2, H-6), 3.56 (2H, s, CH ₂C₆H₄CN),3.01 (1H, m, 1H of BnpipH-2, H-6), 2.81 (2H, m, 2H of pipH-2, H-6) 2.71(1H, m, 1H of BnpipH-2, H-6), 2.22 (2H, dd, J 11.5, 10.0 Hz, 2H ofpipH-2, H-6), 2.00 (2H, m, 2H of pipH-3, H-5), 1.86 (1H, m, BnpipH-4),1.62 (2H, m, 2H of pipH-3, H-5), 1.44-1.30 (4H, m, 4H of BnpipH-3, H-5);m/z: 556 [M+H]⁺.

Compound 143:N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-methoxyphenoxy)piperidine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 8.60 (1H, d, J 1.5 Hz, pyH-6), 8.24 (1H, d, J 8.0 Hz,pyH-3), 7.92 (1H, d, J 8.5 Hz, NH), 7.88 (1H, dd, J 8.0, 2.0 Hz, pyH-4),7.61 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.45 (2H, d, J 8.5 Hz, 2H ofC₆H₄CN), 6.87 (2H, d, J 9.0 Hz, 2H of C₆ H ₄OCH₃), 6.82 (2H, d, J 9.0Hz, 2H of C₆ H ₄OCH₃), 4.47 (1H, m, 1H of oxypip), 4.00 (1H, m, pipH-4),3.88 (2H, m, 2H of oxypip), 3.77 (3H, s, OCH₃), 3.63 (1H, m, 1H ofoxypip), 3.56 (2H, s, CH ₂C₆H₄CN), 3.35 (1H, m, 1H of oxypip), 2.81 (2H,m, 2H of pip), 2.23 (2H, dd, J 11.0, 10.0 Hz, 2H of pip), 2.01 (4H, m,2H of pip, 2H of oxypip), 1.82 (2H, m, 2H of oxypip), 1.63 (2H, m, 2H ofpip); m/z: 555 [M+H]⁺.

Compound 144:N2-(2-(4-cyanobenzyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N-5-(4-fluorobenzyl)pyridine-2,5-dicarboxamide.¹H nmr (CDCl₃) δ 9.86 (1H, s, IsoqH-8), 8.99 (1H, d, J 1.0 Hz, pyH-6),8.28 (1H, d, J 8.0 Hz, pyH-3), 8.22 (1H, dd, J 8.0, 1.5 Hz, pyH-4), 7.51(2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.51 (2H, d, J 8.5 Hz, 2H of C₆H₄CN),7.42 (1H, dd, J 8.5, 1.5 Hz, IsoqH-6), 7.33 (2H, m, 2H of C₆H₄F), 7.12(1H, d, J 8.5 Hz, IsoqH-5), 7.04 (2H, t, J 8.5 Hz, 2H of C₆H₄F), 6.71(1H, t, J 5.5 Hz, NH), 4.63 (2H, d, J 6.0 Hz, NHCH₂C₆H₄F), 3.72 (2H, s,IsoqH-1 of CH₂C₆H₄CN), 3.62 (2H, s, IsoqH-1 or CH₂C₆H₄CN), 2.89 (2H, t,J 5.5 Hz, IsoqH-3 or IsoqH-4), 2.75 (2H, t, J 6.0 Hz, IsoqH-3 or H-4);m/z: 520 [M+H]⁺.

Compound 145:N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-methylbenzyl)piperidine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 8.56 (1H, s, pyH-6), 8.21 (1H, d, J 8.0 Hz, pyH-3),7.93 (1H, d, J 8.5 Hz, NH), 7.84 (1H, dd, J 8.0, 1.5 Hz, pyH-4), 7.61(2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.46 (2H, d, J 8.5 Hz, 2H of C₆H₄CN),7.09 (2H, d, J 8.0 Hz, 2H of C₆H₄CH₃), 7.02 (2H, d, J 8.0 Hz, 2H ofC₆H₄CH₃), 4.69 (1H, m, 1H of BnpipH-2, H-6), 4.01 (1H, m, pipH-4), 3.60(1H, m, 1H of BnpipH-2, H-6), 3.58 (2H, s, CH₂C₆H₄CN), 3.00 (1H, m, 1Hof BnpipH-2, H-6), 2.82 (2H, m, 2H of pipH-2, H-6), 2.74 (1H, m, 1H ofBnpipH-2, H-6), 2.53 (2H, m, CH₂C₆H₄CH₃), 2.04 (3H, s, CH₃), 2.24 (2H,t, J 11.0 Hz, 2H of pipH-2, H-6), 2.01 (2H, m, 2H of pipH-3, H-5),1.79-1.63 (4H, m, 2H of pipH-3, H-5, BnpipH-4′, 1H of BnpipH-3, H-5),1.31-1.13 (3H, m, 3H of BnpipH-3, H-5); m/z: 537 [M+H]⁺.

Compound 146:N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(3-fluoro-4-methoxybenzyl)piperidine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 8.56 (1H, m, pyH-6), 8.22 (1H, d, J 8.0 Hz, pyH-3),7.92 (1H, d, J 8.5 Hz, NH), 7.85 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.61(2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.46 (2H, d, J 8.5 Hz, 2H of C₆H₄CN),7.20 (1H, t, 8.0 Hz, 1×ArH), 6.73 (1H, dd, J 8.0, 7.0 Hz, 1×ArH), 6.68(1H, br s, 1×ArH), 4.69 (1H, m, 1H of Bnpip), 4.00 (1H, m, pipH-4), 3.79(3H, s, OCH₃), 3.62 (1H, m, 1H of Bnpip), 3.56 (2H, s, CH₂C₆H₄CN), 3.01(1H, m, 1H of Bnpip), 2.81 (2H, m, 2H of pip), 2.75 (1H, m, 1H ofBnpip), 2.55 (2H, t, J 6.0 Hz, CH₂C₆H₃FOCH₃), 2.23 (2H, dd, J 11.0, 9.5Hz, 2H of pip), 2.01 (2H, m, 2H of pip), 1.82 (2H, m, 2H of Bnpip), 1.64(2H, m, 2H of pip), 1.33-1.18 (3H, m, 3H of Bnpip); m/z: 570 [M+H]⁺.

Compound 147:N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(3-methoxybenzyl)piperidine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 8.56 (1H, br s, pyH-6), 8.22 (1H, d, J 8.0 Hz, pyH-3),7.92 (1H, d, J 8.5 Hz, NH), 7.84 (1H, br d, J 8.0 Hz, pyH-4), 7.61 (2H,d, J 8.0 Hz, 2H of C₆H₄CN), 7.46 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.85(4H, m, 4H of C₆H₄OCH₃), 4.69 (1H, m, 1H of BnpipH-2, H-6), 3.99 (1H, m,pipH-4), 3.86 (3H, s, OCH₃), 3.62 (1H, m, 1H of BnpipH-2, H-6), 3.56(2H, s, CH ₂C₆H₄CN), 3.02 (1H, m, 1H of BnpipH-2, H-6), 2.81 (2H, m, 2Hof pipH-2, H-6), 2.75 (1H, m, 1H of BnpipH-2, H-6), 2.51 (2H, m, CH₂C₆H₄OCH₃), 2.23 (2H, dd, J 11.0, 9.5 Hz, 2H of pipH-2, H-6), 2.01 (2H,m, 2H of pipH-3, H-5), 1.77 (2H, m, 2H of BnpipH-3, H-4, H-5), 1.64 (2H,m, 2H of pipH-3, H-5), 1.30-1.16 (3H, m, 3H of BnpipH-3, H-4, H-5); m/z:552 [M+H]⁺.

Compound 148:N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-fluorophenoxy)piperidine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 8.60 (1H, s, pyH-6), 8.23 (1H, d, J 8.0 Hz, pyH-3),7.92 (1H, d, J 8.5 Hz, NH), 7.88 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.61(2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.46 (2H, d, J 8.0 Hz, 2H of C₆H₄CN),6.98 (2H, dd, J 9.5, 8.0 Hz, 2H of C₆H₄F), 6.86 (2H, m, 2H of C₆H₄F),4.52 (1H, m, oxypipH-4), 4.01 (1H, m, pipH-4), 3.88 (2H, m, 2H ofoxypipH-2, H-6), 3.64 (1H, m, 1H of oxypipH-2, H-6), 3.58 (2H, s,CH₂C₆H₄CN), 3.32 (1H, m, 1H of oxypipH-2, H-6), 2.83 (2H, m, 2H ofpipH-2, H-6), 2.24 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 2.01 (3H, m,2H of pipH-3, H-5, 1H of oxypipH-3, H-5), 1.83 (3H, m, 3H of oxypipH-3,H-5), 1.66 (2H, m, 2H of pipH-3, H-5); m/z: 542 [M+H]⁺.

Compound 149:N2-(1-(4-cyanobenzyl)piperidin-4-yl)-N-5-(2-(4-fluorophenoxy)ethyl)pyridine-2,5-dicarboxamide.¹H nmr (CDCl₃) δ 8.94 (1H, s, pyH-6), 8.25 (1H, d, J 8.0 Hz, pyH-3),8.19 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.95 (1H, d, J 8.5 Hz, NHpip), 7.61(2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.45 (2H, d, J 8.5 Hz, 2H of C₆H₄CN),6.98 (2H, dd, J 9.5, 8.0 Hz, 2H of C₆H₄F), 6.85 (2H, dd, J 9.5, 4.5 Hz,2H of C₆H₄F), 6.67 (1H, br s, NHCH₂CH₂O), 4.13 (2H, t, J 5.0 Hz, NHCH₂CH₂O), 4.00 (1H, m, pipH-4), 3.89 (2H, q, J 5.5 Hz, NHCH ₂CH₂O), 3.56 (2H,s, CH ₂C₆H₄CN), 2.81 (2H, m, 2H of pipH-2, H-6), 2.23 (2H, dd, J 11.5,11.0 Hz, 2H of pipH-2, H-6), 2.02 (2H, m, 2H of pipH-3, H-5), 1.69 (2H,m, 2H of pipH-3, H-5); m/z: 502 [M+H]⁺.

Compound 150:N-(cis-4-(4-cyanophenoxy)cyclohexyl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 8.58 (1H, m, pyH-6), 8.23 (1H, dd, J 8.0, 1.0 Hz,pyH-3), 7.99 (1H, d, J 8.5 Hz, NH), 7.86 (1H, dd, J 8.0, 2.0 Hz, pyH-4),7.58 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 7.26 (2H, m, 2H of C₆H₄F), 7.00(2H, t, J 8.5 Hz, 2H of C₆H₄F), 6.95 (2H, d, J 9.0 Hz, 2H of C₆H₄CN),4.59 (1H, br s, cHexH-1), 4.10 (1H, m, cHexH-4), 3.80 (2H, m, 2H ofpiz), 3.50 (2H, s, CH2C6H4F), 3.39 (2H, m, 2H of piz), 2.53 (2H, m, 2Hof piz), 2.38 (2H, m, 2H of piz), 2.06 (2H, m, 2H of cHexH-2, H-6),1.90-1.72 (4H, m, 2H of cHexH2, H-6, 2H of cHexH-3, H-5), 1.24 (2H, m,2H of cHexH-3, H-5); m/z: 542 [M+H]⁺.

Compound 151:N-(trans-4-(4-cyanophenoxy)cyclohexyl)-5-(4-(4-fluorobenzoyl)piperazine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 8.60 (1H, m, pyH-6), 8.25 (1H, d, J 8.0 Hz, pyH-3),8.02-7.96 (3H, m, 2H of C₆H₄F, NH), 7.89 (1H, dd, J 8.0, 2.0 Hz, pyH-4),7.58 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 7.16 (2H, t, J 8.5 Hz, 2H ofC₆H₄F), 6.96 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 4.66 (1H, m, 1H of pipH-2,H-6), 4.60 (1H, br s, cHexH-1), 4.10 (1H, m, cHexH-4), 3.76 (1H, m, 1Hof pipH-2, H-6), 3.54 (1H, m, pipH-4), 3.24 (1H, m, 1H of pipH-2, H-6),3.11 (1H, m, 1H of pipH-2, H-6), 2.07 (3H, m, 3H of cHexH-2, H-6),1.90-1.79 (8H, m, 1H of cHexH-2, H-6, 3H of cHexH-3, H-5, 4H of pipH-3,H-5), 1.25 (1H, m, 1H of cHexH-3, H-5); m/z: 555 [M+H]⁺.

Compound 152:N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(3-(4-fluorobenzyl)piperidine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 8.48 (1H, br s, pyH-6), 8.17 (1H, d, J 8.0 Hz, NH orpyH-3), 7.87 (1H, d, J 7.5 Hz, NH or pyH-3), 7.80 (1H, m, pyH-4), 7.60(2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.46 (2H, d, J 8.5 Hz, 2H of C₆H₄CN),7.03 (2H, m, 2H of C₆H₄F), 6.93 (2H, m, 2H of C₆H₄F), 4.52 (1H, br s, 1Hof Bnpip), 4.02 (1H, m, pipH-4), 3.57 (2H, s, CH ₂C₆H₄CN), 2.95 (1H, m,1H of Bnpip), 2.81 (2H, m, 2H of pip), 2.68 (1H, dd, J 13.0, 10.5 Hz, 1Hof Bnpip), 2.50 (1H, m, 1H of Bnpip), 2.26 (2H, td, J 11.5, 2.0 Hz, 2Hof pip), 2.04 (2H, m, 2H of pip), 1.90-1.58 (5H, m, 2H of pip, 3H ofBnpip), 1.27 (2H, m, 2H of Bnpip); m/z: 541 [M+H]⁺. ** 2H of Bnpipmissing, probably due to broadness of the peak in the 3-5 region **

Compound 153:N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(2-(4-fluorobenzyl)piperidine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 8.19 (1H, br s, pyH-6), 8.10 (1H, d, J 7.5 Hz, 1H ofNH, pyH-3 or pyH-4), 7.86 (1H, d, J 8.0 Hz, 1H of NH, pyH-3 or pyH-4),7.60 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.46 (2H, d, J 8.0 Hz, 2H ofC₆H₄CN), 7.05 (2H, m broad, 2H of C₆H₄F), 6.96 (2H, t, J 8.0 Hz, 2H ofC₆H₄F), 4.00 (1H, m, pipH-4), 3.57 (2H, s, CH2C6H4CN), 3.08 (2H, m, 2Hof Bnpip), 2.80 (3H, m, 2H of pip, 1H of Bnpip), 2.25 (2H, m, 2H ofpip), 2.02 (2H, m, 2H of pip), 1.76-1.60 (8H, m, 2H of pip, 6H ofBnpip); m/z: 540 [M+H]⁺. **2H of Bnpip not showing up, probably toobroad to observe**

Compound 154:5-(4-(4-chlorobenzoyl)piperidine-1-carbonyl)-N-(1-(4-cyanobenzyl)piperidin-4-yl)picolinamide.¹H nmr (CDCl₃) δ 8.60 (1H, m, pyH-6), 8.24 (1H, dd, J 8.0, 0.5 Hz,pyH-3), 7.94-7.87 (4H, m, NH, pyH-4, 2H of C₆H₄Cl), 7.61 (2H, d, J 8.0Hz, 2H of C₆H₄CN), 7.46 (4H, m, 2H of C₆H₄CN, 2H of C₆H₄Cl), 4.65 (1H,m, 1H of BzpipH-2, H-6), 4.01 (1H, m, pipH-4), 3.77 (1H, m, 1H ofBzpipH-2, H-6), 3.58 (2H, s, CH ₂C₆H₄CN), 3.53 (1H, m, BzpipH-4), 3.17(2H, m 2H of BzpipH-2, H-6), 2.83 (2H, m, 2H of pipH-2, H-6), 2.24 (2H,t, J 10.5 Hz, 2H of pipH-2, H-6), 2.02 (2H, m, 2H of BzpipH-3, H-5),1.82 (2H, m, 2H of pipH-3, H-5), 1.71-1.61 (4H, m, 2H of pipH-3, H-5, 2Hof BzpipH-3, H-5); m/z: 570 [M+H]⁺.

Compound 155:N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(3-cyanophenoxy)piperidine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 8.60 (1H, m, pyH-6), 8.24 (1H, d, J 8.0 Hz, pyH-3),7.92 (1H, d, J 8.5 Hz, NH), 7.89 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.61(2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.46 (2H, d, J 8.0 Hz, 2H of C₆H₄CN),7.39 (1H, t, J 7.5 Hz, 1H of OC₆H₄CN), 7.26 (1H, m, 1H of OC₆H₄CN), 7.14(2H, m, 2H of OC₆H₄CN), 4.65 (1H, m, PhoxypipH-4), 4.01 (1H, m, pipH-4),3.90 (2H, m, 2H of PhoxypipH-2, H-6), 3.63 (1H, m, 1H of PhoxypipH-2,H-6), 3.56 (2H, s, CH ₂C₆H₄CN), 3.39 (1H, m, 1H of PhoxypipH-2, H-6),2.81 (2H, m, 2H of pipH-2, H-6), 2.22 (2H, dd, J 11.0, 10.0 Hz, 2H ofpipH-2, H-6), 2.04-1.70 (6H, m, 2H of pipH-3, H-5, PhoxypipH-3, H-5),1.64 (2H, m, 2H of pipH-3, H-5); m/z: 549 [M+H]⁺.

Compound 156:5-(4-(3-chloro-4-cyanophenoxy)piperidine-1-carbonyl)-N-(1-(4-cyanobenzyl)piperidin-4-yl)picolinamide.¹H nmr (CDCl₃) δ 8.60 (1H, m pyH-6), 8.25 (1H, d, J 8.0 Hz, pyH-3), 7.91(1H, m, NH), 7.89 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.61 (2H, d, J 8.5 Hz,2H of C₆H₄CN), 7.59 (1H, d, J 9.0 Hz, H-5 or H-6 of C₆H₃ClCN), 7.45 (2H,d, J 8.0 Hz, 2H of C₆H₄CN), 7.03 (1H, d, J 2.0 Hz, H-2 of C₆H₃ClCN),6.87 (1H, dd, J 8.5, 2.0 Hz, H-5 or H-6 of C₆H₃ClCN), 4.69 (1H, m,PhoxypipH-4), 4.01 (1H, m, pipH-4), 3.91 (2H, m, 2H of PhoxypipH-2,H-6), 3.62 (1H, m, 1H of PhoxypipH-2, H-6), 3.56 (2H, s, CH ₂C₆H₄CN),3.42 (1H, m, 1H of PhoxypipH-2, H-6), 2.82 (2H, m, 2H of pipH-2, H-6),2.23 (2H, dd, J 11.5, 10.0 Hz, 2H of pipH-2, H-6), 2.04-1.69 (6H, m, 2Hof pipH-3, H-5, PhoxypipH-3, H-5), 1.64 (2H, m, 2H of pipH-3, H-5); m/z:583, 585 [M+H]⁺.

Compound 157:N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-(trifluoromethyl)phenoxy)piperidine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 8.60 (1H, m, pyH-6), 8.24 (1H, d, J 8.0 Hz, pyH-3),7.94-7.87 (2H, m, NH, pyH-4), 7.61 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.55(2H, m, 2H of C₆H₄CF₃), 7.46 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 6.97 (2H,d, J 9.0 Hz, 2H of C₆H₄CF₃), 4.70 (1H, m, 1H of Phoxypip), 4.01 (1H, m,1H of Phoxypip or pipH-4), 3.95-3.87 (1H, m, 1H of Phoxypip or pipH-4),3.64 (1H, m, 1H of Phoxypip), 3.58 (2H, s, CH ₂C₆H₄CN), 3.50 (1H, m, 1Hof Phoxypip), 3.35 (1H, m, 1H of Phoxypip), 2.83 (2H, m, 2H of pip),2.24 (2H, t, J 11.0 Hz, 2H of pip), 2.14-1.84 (6H, m, 2H of pip, 4H ofPhoxypip), 1.65 (2H, m, 2H of pip); m/z: 592 [M+H]⁺.

Compound 158:N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(3,4-difluorophenoxy)piperidine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 8.60 (1H, m, pyH-6), 8.24 (1H, d, J 8.0 Hz, pyH-3),7.91 (1H, m, NH), 7.88 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.61 (2H, d, J8.0 Hz, 2H of C₆H₄CN), 7.45 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.07 (1H,q, J 9.5 Hz, H-5 of C₆H₃F₂), 6.74 (1H, m, H-1 of C₆H₃F₂), 6.61 (1H, m,H-6 of C₆H₃F₂), 4.51 (1H, m, PhoxypipH-4), 4.01 (1H, m, pipH-4), 3.88(2H, m, 2H of PhoxyH-2, H-6), 3.63 (1H, m, 1H of PhoxypipH-2, H-6), 3.56(2H, s, CH ₂C₆H₄CN), 3.37 (1H, m, 1H of PhoxypipH-2, H-6), 2.82 (2H, m,2H of pipH-2, H-6), 2.22 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6),2.04-1.84 (6H, m, 2H of pipH-3, H-5, 4H of PhoxypipH-3, H-5), 1.64 (2H,m, 2H of pipH-3, H-5); m/z: 560 [M+H]⁺.

Compound 159:N-(1-(4-cyanobenzyl)piperidin-4-yl)-3-(5,20-dioxo-24-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-7,10,13,16-tetraoxa-4,19-diazatetracos-1-ynyl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide.Hydrogen chloride (0.054 mL of a 4.0M solution in dioxane, 0.216 mmol,5.0 eq) was added to a solution of Compound 164 (see below) (0.030 g,0.043 mmol, 1.0 eq) in dichloromethane (1.0 mL). The reaction mixturewas stirred at room temperature for 90 minutes before removing thesolvent under a stream of nitrogen. The residue was dried under vacuumto provide3-(3-aminoprop-1-ynyl)-N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamidetrihydrochloride, which was used without further purification; m/z 594[M+H]⁺. To a suspension of the3-(3-aminoprop-1-ynyl)-N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamidetrihydrochloride (0.043 mmol, 1.0 eq) in dichloromethane (1.0 mL) wasadded triethylamine (0.018 mL, 0.129 mmol, 3.0 eq) forming a brownsolution. 15-[(D)-(+)-Biotinylamino]-4,7,10,13-tetraoxapentadecanoicacid (0.023 g, 0.047 mmol, 1.1 eq) and HATU (0.018 g, 0.047 mmol, 1.1eq) were added followed by dimethylaminopyridine (0.005 g, 0.043 mmol,1.0 eq). The reaction was stirred at room temperature for 3 hours beforepouring into water (20 mL). The organics were extracted with CH₂Cl₂(3×25 mL). The combined organics were washed with brine (35 mL), dried(Na₂SO₄) and concentrated under reduced pressure. The crude material waspurified by RP-HPLC to provide Compound 159; m/z 1068 [M+H]⁺.

Compound 160:5-(4-(4-fluorobenzoyl)piperidine-1-carbonyl)-N-(1-(4-methoxybenzyl)piperidin-4-yl)picolinamide.To a solution of 5-(methoxycarbonyl)pyridine-2-carboxylic acid (0.209 g,1.18 mmol, 1.0 eq) and 1-(4-methoxybenzyl)piperidine dihydrochloride(0.373 g, 1.27 mmol, 1.1 eq) in dimethylformamide (10 mL) was addedtriethylamine (0.40 mL, 2.89 mmol, 2.5 eq) followed by HATU (0.528 g,1.39 mmol, 1.2 eq). The reaction was stirred at room temperature for 2days before partitioning between EtOAc (100 mL) and water (80 mL). Theorganics were further washed with brine (80 mL), water (80 mL) and brine(80 mL), before drying (Na₂SO₄) and concentrating under reduced pressureto yield methyl 6-(1-(4-methoxybenzyl)piperidin-4-ylcarbamoyl)nicotinateas a white solid (0.378 g, 84%) which was used without furtherpurification; ¹H nmr (CDCl₃) 9.13 (1H, m, pyH-6), 8.43 (1H, dd, J 8.0,2.0 Hz, pyH-4), 8.25 (1H, d, J 8.0 Hz, pyH-3), 7.98 (1H, d, J 7.5 Hz,NH), 7.26 (2H, d, J 8.5 Hz, 2H of C₆H₄OCH₃), 6.87 (2H, d, J 8.5 Hz, 2Hof C₆H₄OCH₃), 4.01 (1H, m, pipH-4), 3.98 (3H, s, 1×OCH₃), 3.80 (3H, s,1×OCH₃), 3.53 (2H, s, CH ₂C₆H₄OCH₃), 2.90 (2H, m, 2H of pip), 2.24 (2H,dd, J 11.0, 10.0 Hz, 2H of pip), 2.02 (2H, m, 2H of pip), 1.69 (2H, m,2H of pip); m/z 384 [M+H]⁺. To a solution of the methyl6-(1-(4-methoxybenzyl)piperidin-4-ylcarbamoyl)nicotinate (0.378 g, 0.987mmol, 1.0 eq) in tetrahydrofuran (6 mL) and methanol (3 mL) was added asolution of lithium hydroxide monohydrate (0.166 g, 3.948 mmol, 4.0 eq)in water (3 mL). The reaction mixture was stirred at room temperaturefor 30 minutes before neutralizing with HCl (approximately 2.0 mL of a2M solution). The reaction was concentrated to dryness to yield6-(1-(4-methoxybenzyl)piperidin-4-ylcarbamoyl)nicotinic acid as a whitesolid, which was used without purification. To a mixture of the6-(1-(4-methoxybenzyl)piperidin-4-ylcarbamoyl)nicotinic acid (0.036 g,0.098 mmol, 1.0 eq), 4-fluorobenzoylpiperidine hydrochloride (0.029 g,0.117 mmol, 1.2 eq), and triethylamine (0.034 mL, 0.244 mmol, 2.5 eq) indimethylformamide (1.0 eq) was added HATU (0.041 g, 0.244 mmol, 1.1 eq).The reaction was shaken at room temperature for 3 hours before addingwater (5 mL). A gum formed, which was dissolved in EtOAc-CH₂Cl₂ (4:1, 50mL). The solution was washed with NaHCO₃-water (1:1, 50 mL), brine (50mL), water (50 mL) and brine (50 mL). The organics were dried (Na₂SO₄)and concentrated under reduced pressure. Column chromatography (silica,3→7% MeOH—CH₂Cl₂) yielded Compound 160 as a colourless oil (0.037 g,68%); ¹H nmr (CDCl₃) δ 8.60 (1H, m, pyH-6), 8.24 (1H, d, J 8.0 Hz,pyH-3), 7.98 (2H, dd, J 8.5, 5.5 Hz, 2H of C₆H₄F), 7.91 (1H, m, NH),7.88 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.24 (2H, d, 2H of C₆H₄OCH₃), 7.16(2H, t, J 8.5 Hz, 2H of C₆H₄F), 6.86 (2H, d, J 8.5 Hz, 2H of C₆H₄OCH₃),4.66 (1H, m, BzpipH-4), 3.99 (1H, m, pipH-4), 3.80 (3H, s, OCH₃), 3.77(1H, m, 1H of BzpipH-2, H-6), 3.54 (1H, m, 1H of BzpipH-2, H-6), 3.48(2H, s, CH ₂C₆H₄OCH₃), 3.21-3.11 (2H, m, 2H of BzpipH-2, H-6), 2.86 (2H,m, 2H of pipH-2, H-6), 2.19 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 2.00(2H, m, 2H of pipH-3, H-5), 1.82 (4H, m, BzpipH-3, H-5), 1.64 (2H, m, 2Hof pipH-3, H-5); m/z: 559 [M+H]⁺.

Compound 161:5-(4-(4-fluorophenoxy)piperidine-1-carbonyl)-N-(1-(4-methoxybenzyl)piperidin-4-yl)picolinamide.¹H nmr (CDCl₃) δ 8.59 (1H, m, pyH-6), 8.23 (1H, d, J 8.0 Hz, pyH-3),7.91 (1H, m, NH), 7.88 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.24 (2H, d, J8.5 Hz, 2H of C₆H₄OCH₃), 6.98 (2H, dd, J 9.0, 8.5 Hz, 2H of C₆H₄F), 6.86(4H, m, 2H of C₆H₄F, 2H of C₆H₄OCH₃), 4.51 (1H, m, PhOpipH-4), 4.00 (1H,m, pipH-4), 3.88 (2H, m, 2H of PhOpipH-2, H-6), 3.80 (3H, s, OCH₃), 3.63(1H, m, 1H of PhOpipH-2, H-6), 3.49 (2H, s, CH ₂C₆H₄OCH₃), 3.34 (1H, m,1H of PhOpipH-2, H-6), 2.87 (2H, m, 2H of pipH-2, H-6), 2.20 (2H, t, J11.0 Hz, 2H of pipH-2, H-6), 2.06-1.90 (4H, m, 2H of pipH-3, H-5, 2H ofPhOpipH-3, H-5), 1.83 (2H, m, 2H of PhOpipH-3, H-5), 1.65 (2H, m, 2H ofpipH-3, H-5); m/z: 547 [M+H]⁺.

Compound 162:5-(4-(4-cyanophenoxy)piperidine-1-carbonyl)-N-(1-(4-methoxybenzyl)piperidin-4-yl)picolinamide.¹H nmr (CDCl₃) δ 8.59 (1H, d, J 1.0 Hz, pyH-6), 8.24 (1H, d, J 8.0 Hz,pyH-3), 7.90 (1H, m, NH), 7.87 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.59 (2H,d, J 9.0 Hz, 2H of C₆H₄CN or C₆H₄OCH₃), 7.23 (2H, d, J 9.0 Hz, 2H ofC₆H₄CN or C₆H₄OCH₃), 6.96 (2H, d, J 9.0 Hz, 2H of C₆H₄CN or C₆H₄OCH₃),6.86 (2H, d, J 9.0 Hz, 2H of C₆H₄CN or C₆H₄OCH₃), 4.70 (1H, m,PhOpipH-4), 3.99 (1H, m, pipH-4), 3.90 (2H, m, 2H of PhOpipH-2, H-6),3.80 (3H, s, OCH₃), 3.64 (1H, m, 1H of PhOpipH-2, H-6), 3.48 (2H, s,CH₂C₆H₄OCH₃), 3.41 (1H, m, 1H of PhOpipH-2, H-6), 2.87 (2H, m, 2H ofpipH-2, H-6), 2.19 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 2.04-1.82 (6H,m, 2H of pipH-3, H-5 and 4H of PhOpipH-3, H-5), 1.64 (2H, m, 2H ofpipH-3, H-5); m/z: 555 [M+H]⁺.

Compound 163:5-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)-N-(1-(4-methoxybenzyl)piperidin-4-yl)picolinamide.¹H nmr (CDCl₃) δ 8.59 (1H, m, pyH-6), 8.23 (1H, d, J 8.0 Hz, pyH-3),7.94 (1H, d, J 9.0 Hz, 2H of OC₆H₄CN or CH₂C₆H₄CN), 7.88 (1H, dd, J 8.0,2.0 Hz, pyH-4), 7.26 (2H, d, J 8.5 Hz, 2H of OC₆H₄CN or CH₂C₆H₄CN), 6.96(2H, d, J 9.0 Hz, 2H of OC₆H₄CN or CH₂C₆H₄CN), 6.86 (2H, d, J 8.5 Hz, 2Hof OC₆H₄CN or CH₂C₆H₄CN), 4.65 (1H, m, PhOpipH-4), 4.01 (1H, m, pipH-4),3.88 (3H, s, OCH₃), 3.80 (1H, m, 1H of PhOpipH-2, H-6), 3.53 (3H, m, 1Hof PhOpipH-2, H-6, CH ₂C₆H₄OCH₃), 3.24-3.11 (2H, m, 2H of PhOpipH-2,H-6), 2.91 (2H, m, 2H of pipH-2, H-6), 2.25 (2H, t, J 11.0 Hz, 2H ofpipH-2, H-6), 2.02 (2H, m, 2H of pipH-3, H-5), 1.89-1.76 (4H, m, 4H ofPhOpipH-3, H-5), 1.70 (2H, m, 2H of pipH-3, H-5); m/z: 572 [M+H]⁺.

Compound 164: tert-butyl3-(2-(1-(4-cyanobenzyl)piperidin-4-ylcarbamoyl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)pyridin-3-yl)prop-2-ynylcarbamate.To a solution of 5-chloro-6-(ethoxycarbonyl)nicotinic acid (0.201 g,0.875 mmol, 1.0 eq) and 4-fluorobenzylpiperazine (0.204 g, 1.051 mmol,1.2 eq) in dimethylformamide (4.0 mL) was added triethylamine (0.146 mL,1.051 mmol, 1.2 eq) followed by HATU (0.366 g, 0.963 mmol, 1.1 eq). Thereaction was shaken at room temperature for 3 hours before partitioningbetween EtOAc (80 mL) and water-NaHCO₃ (2:1, 60 mL). The organics werefurther washed with brine (80 mL), water (80 mL) and brine (80 mL)before drying (Na₂SO₄) and concentrating under reduced pressure. MPLC(30→95% EtOAc-hexane, 2→25 min) yielded ethyl3-chloro-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinate as awhite solid (0.265 g, 75%); ¹H nmr (D₆-DMSO) 8.54 (1H, d, J 1.5 Hz,pyH-2 or pyH-4), 7.83 (1H, d, J 1.0 Hz, pyH-2 or pyH-4), 7.26 (2H, m, 2Hof C₆H₄F), 6.99 (2H, t, J 8.5 Hz, 2H of C₆H₄F), 4.48 (2H, q, J 7.0 Hz,OCH ₂CH₃), 3.55 (4H, m, 4H of piz), 2.45 (4H, m, 4H of piz), 1.43 (3H,t, J 7.0 Hz, OCH₂CH ₃); m/z 406, 408 [M+H]⁺. A solution of the ethyl3-chloro-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinate (0.265 g,0.654 mmol, 1.0 eq) and N-Boc-propargylamine (0.122 g, 0.785 mmol, 1.2eq) in dimethylformamide (7.0 mL) was degassed by bubbling argon throughit. Triethylamine (0.14 mL, 0.981 mmol, 1.5 eq) was added followed bycopper (I) iodide (0.006 g, 0.033 mmol, 0.05 eq) andtetrakis(triphenylphosphine)palladium (0.038 g, 0.033 mmol, 0.05 eq).The reaction mixture was further degassed before heating to 90° C. for14 hours. The reaction was cooled and filtered through Celite®, elutingwith EtOAc (80 mL). The filtrate was washed with water (100 mL), brine(80 mL), water (100 mL) and brine (80 mL). The organics were dried(Na₂SO₄) and concentrated under reduced pressure. Column chromatography(silica, 70% EtOAc-hexane) yielded the ethyl3-chloro-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinate startingmaterial and ethyl3-(3-(tert-butoxycarbonylamino)prop-1-ynyl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinateas a colourless oil; ¹H nmr (CDCl₃) 8.60 (1H, d, J 2.0 Hz, pyH-2 orpyH-4), 7.87 (1H, d, J 2.0 Hz, pyH-2 or pyH-4), 7.26 (2H, m, 2H ofC₆H₄F), 6.99 (2H, t, J 8.5 Hz, 2H of C₆H₄F), 4.87 (1H, br s, NH), 4.47(2H, q, J 7.0 Hz, OCH ₂CH₃), 4.21 (2H, d, J 5.5 Hz, CH ₂NHBoc), 3.77(2H, m, 2H of piz), 3.37 (2H, m, 2H of piz), 2.51 (2H, m, 2H of piz),2.38 (2H, m, 2H of piz), 1.47 (9H, s, C(CH₃)₃), 1.43 (3H, t, J 7.0 Hz,OCH₂CH ₃); m/z 525 [M+H]⁺. A solution of lithium hydroxide monohydrate(0.010 g, 0.229 mmol, 2.0 eq) in water (0.5 mL) was added to a solutionof the ethyl3-(3-(tert-butoxycarbonylamino)prop-1-ynyl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinate(0.060 g, 0.115 mmol, 1.0 eq) in tetrahydrofuran-methanol (2:1, 1.5 mL).The reaction was stirred at room temperature for 40 minutes beforeneutralizing with HCl (approximately 0.2 mL of a 2M solution). Thereaction mixture was concentrated to dryness to provide3-(3-(tert-butoxycarbonylamino)prop-1-ynyl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinicacid, which was used without purification; m/z 497 [M+H]⁺. To a solutionof the crude3-(3-(tert-butoxycarbonylamino)prop-1-ynyl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinicacid (0.115 mmol, 1.0 eq) in dimethylformamide (2.0 mL) was added1-(4-cyanobenzyl)-4-aminopiperidine dihydrochloride (0.040 g, 0.138mmol, 1.2 eq) and HATU (0.052 g, 0.138 mmol, 1.2 eq). Triethylamine(0.056 mL, 0.403 mmol, 3.5 eq) was added and the reaction mixture wasstirred at room temperature for 2.5 hours before partitioning betweenEtOAc (100 mL) and water (100 mL). The organics were further washed withbrine (80 mL), water (80 mL) and brine (80 mL), dried (Na₂SO₄) andconcentrated under reduced pressure. Column chromatography (silica, 3→6%MeOH—CH₂Cl₂) yielded Compound 164 as a yellow foam; ¹H nmr (CDCl₃) δ8.46 (1H, d, J 2.0 Hz, pyH-4 or pyH-6), 7.85 (1H, d, J 2.0 Hz, pyH-4 orpyH-6), 7.80 (1H, d, J 8.0 Hz, CONH), 7.60 (2H, d, J 8.0 Hz, 2H ofC₆H₄CN), 7.45 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.29-7.25 (2H, m, 2H ofC₆H₄F), 7.00 (2H, t, J 8.5 Hz, 2H of C₆H₄F), 4.88 (1H, m, NHCO₂C), 4.23(2H, d, J 5.5 Hz, CCH₂NH), 3.99 (1H, m, pipH-4), 3.80-3.40 (4H, br m, 4Hof piz), 3.56 (2H, s, CH ₂C₆H₄CN or CH ₂C₆H₄F), 3.51 (2H, s, CH ₂C₆H₄CNor CH ₂C₆H₄F), 2.80 (2H, m, 2H of pip), 2.46 (4H, m, 4H of piz), 2.23(2H, t, J 11.0 Hz, 2H of pip), 2.01 (2H, m, 2H of pip), 1.63 (2H, m, 2Hof pip), 1.46 (9H, s, C(CH₃)₃); m/z: 694 [M+H]⁺.

Compound 165:N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-cyanophenoxy)piperidin-1-yl)picolinamide.To a solution of 5-bromopicolinic acid (0.50 g, 2.48 mmol, 1.0 eq) and1-(4-cyanobenzyl)-4-aminopiperidine dihydrochloride (0.71 g, 2.48 mmol,1.0 eq) in dimethylformamide (10 mL) was added triethylamine (1.21 mL,8.66 mmol, 3.5 eq) and HATU (1.13 g, 2.97 mmol, 1.2 eq). The reactionmixture was stirred at room temperature 14 hours before partitioningbetween EtOAc (120 mL) and water (100 mL). The organics were washed withbrine (100 mL), water (100 mL) and brine (100 mL), dried (Na₂SO₄) andconcentrated under reduced pressure. MPLC (0%, 5%, 10% MeOH—CH₂Cl₂,0→5→25→35 min) yielded5-bromo-N-(1-(4-cyanobenzyl)piperidin-4-yl)picolinamide as a waxy brownsolid: ¹H nmr (CDCl₃) 8.60 (1H, d, J 2.0 Hz, pyH-6), 8.07 (1H, d, J 8.5Hz, pyH-3), 7.97 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.84 (1H, d, J 7.5 Hz,NH), 7.63 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.50 (2H, d, J 8.0 Hz, 2H ofC₆H₄CN), 4.00 (1H, m, pipH-4), 3.63 (2H, s, CH ₂C₆H₄CN), 2.88 (2H, m, 2Hof pip), 2.30 (2H, m, 2H of pip), 2.04 (2H, m, 2H of pip), 1.70 (2H, m,2H of pip); m/z 399, 401 [M+H]⁺. To a mixture of the5-bromo-N-(1-(4-cyanobenzyl)piperidin-4-yl)picolinamide (0.040 g, 0.100mmol, 1.0 eq) 4-(4-piperidinyloxy)benzonitrile (0.024 g, 0.120 mmol, 1.2eq), sodium t-butoxide (0.019 g, 0.201 mmol, 2.0 eq) and S-Phos (0.004g, 0.010 mmol, 0.1 eq) was added toluene (1.0 mL). The resulting mixturewas degassed by bubbling argon through the mixture.Tris(dibenzylideneacetone)dipalladium (0.005 g, 0.005 mmol, 0.05 eq) wasadded and the mixture further degassed before sealing the reaction andheating to 105° C. for 14 hours. The reaction was filtered throughcelite, eluting with 5% MeOH—CH₂Cl₂ (3×15 mL). The filtrate wasconcentrated under reduced pressure. The crude material was purified byRP-HPLC to yield Compound 165: ¹H nmr (CDCl₃) δ 8.19 (1H, d, J 3.0 Hz,pyH-6), 8.04 (1H, d, J 9.0 Hz, pyH-3), 7.72 (1H, d, J 8.5 Hz, NH), 7.60(4H, m, 2H of OC₆H₄CN, 2H of CH₂C₆H₄CN), 7.45 (2H, d, J 8.0 Hz, 2H ofCH₂C₆H₄CN), 7.24 (1H, dd, J 8.0, 3.0 Hz, pyH-4), 6.97 (2H, d, J 9.0 Hz,2H of OC₆H₄CN), 4.64 (1H, m, PhOpipH-4), 3.98 (1H, m, pipH-4), 3.63-3.57(2H, m, 2H of PhOpipH-2, H-6), 3.55 (2H, s, CH ₂C₆H₄CN), 3.38-3.30 (2H,m, 2H of PhOpipH-2, H-6), 2.80 (2H, m, 2H of pipH-2, H-6), 2.22 (2H, t,J 11.5 Hz, 2H of pipH-2, H-6), 2.16-2.05 (2H, m, 2H of PhOpipH-3, H-5),2.01-1.92 (4H, m, 2H of pipH-3, H-5, 2H of PhOpipH-3, H-5), 1.62 (2H, m,2H of pipH-3, H-5); m/z: 522 [M+H]⁺.

Compound 166:N2-(1-(4-cyanobenzyl)piperidin-4-yl)-N5-(1-(4-cyanophenyl)piperidin-4-yl)pyridine-2,5-dicarboxamide.¹H nmr (CDCl₃) δ 8.92 (1H, d, J 1.0 Hz, pyH-6), 8.22 (1H, d, J 8.0 Hz,pyH-3), 8.16 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.94 (1H, d, J 8.5 Hz,BnpipNH), 7.61 (2H, d, J 8.5 Hz, 2H of CH₂C₆H₄CN), 7.47 (4H, m, 2H ofCH₂C₆H₄CN, 2H of NC₆H₄CN), 6.88 (2H, d, J 9.0 Hz, 2H of NC₆H₄CN), 6.21(1H, d, J 7.5 Hz, PhpipNH), 4.26 (1H, m, PhpipH-4), 3.99 (1H, m,BnpipH-4), 3.89 (2H, m, 2H of PhpipH-2, H-6), 3.56 (2H, s, CH ₂C₆H₄CN),3.08 (2H, t, J 11.5 Hz, 2H of PhpipH-2, H-6), 2.81 (2H, m, 2H ofBnpipH-2, H-6), 2.26-2.16 (4H, m, 2H of PhpipH-3, H-5, 2H of BnpipH-2,H-6), 2.02 (2H, m, 2H of BnpipH-3, H-5), 1.70-1.59 (4H, m, 2H ofPhpipH-3, H-5, 2H of BnpipH-3, H-5); m/z: 548 [M+H]⁺.

Compound 167:N-((cis)-4-(4-cyanophenoxy)cyclohexyl)-5-(4-(4-fluorophenoxy)piperidine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 8.61 (1H, dd, J 2.0, 1.0 Hz, pyH-6), 8.25 (1H, dd, J8.0, 1.0 Hz, pyH-3), 7.99 (1H, d, J 8.5 Hz, NH), 7.89 (1H, dd, J 8.0,2.0 Hz, pyH-4), 7.58 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 7.01-6.94 (4H, m,2H of C₆H₄CN, 2H of C₆H₄F), 6.89-6.84 (2H, m, 2H of C₆H₄F), 4.60 (1H, brs, cHexH-1 or PhOpipH-4), 4.52 (1H, m, cHexH-1 or PhOpipH-4), 4.10 (1H,m, cHexH-4), 3.88 (2H, m, 2H of PhOpipH-2, H-6), 3.64 (1H, m, 1H ofPhOpipH-2, H-6), 3.36 (1H, m, 1H of PhOpipH-2, H-6), 2.11-1.90 (12H, m,cHexH-2, H-3, H-5, H-6, PhOpipH-3, H-5); m/z: 543 [M+H]⁺.

Compound 265:N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(3-(4-cyanophenoxy)piperidin-1-yl)picolinamide.¹H nmr (CDCl₃) δ 8.13 (1H, d, J 3.0 Hz, pyH-6), 8.01 (1H, d, J 9.0 Hz,pyH-3), 7.70 (1H, d, J 8.5 Hz, NH), 7.62-7.57 (4H, 4×ArH), 7.45 (2H, d,J 8.0 Hz, 2H of CH₂C₆H₄CN or OC₆H₄CN), 7.19 (1H, dd, J 9.0, 3.0 Hz,pyH-4), 6.94 (2H, d, J 9.0 Hz, 2H of CH₂C₆H₄CN or OC₆H₄CN), 4.54 (1H, m,PhOpipH-4), 3.98 (1H, m, pipH-4), 3.75 (1H, dd, J 12.5, 3.0 Hz, 1H ofPhOpipH-2, H-6), 3.55 (2H, s, CH ₂C₆H₄CN), 3.49 (1H, m, 1H of PhOpipH-2,H-6), 3.31 (1H, dd, J 13.0, 7.5 Hz, 1H of PhOpipH-2, H-6), 3.23 (1H, m,1H of PhOpipH-2, H-6), 2.80 (2H, m, 2H of pip), 2.22 (2H, dd, J 11.0,10.0 Hz, 2H of pip), 2.14 (1H, m, 1H of PhOpip), 1.99 (3H, m, 2H of pip,1H of PhOpip), 1.79 (2H, m, 2H of PhOpip), 1.62 (2H, m, 2H of pip); m/z:521 [M+H]⁺.

Compound 266:5-(4-(4-chlorobenzoyl)piperidin-1-yl)-N-(1-(4-cyanobenzyl)piperidin-4-yl)picolinamide.¹H nmr (CDCl₃) δ 8.18 (1H, br s, 1×py), 7.98 (1H, d, J 8.5 Hz, NH or1×py), 7.98 (2H, d, J 8.5 Hz, 2H of C₆H₄CN or C₆H₄Cl), 7.96 (1H, m, NHor 1×py), 7.90 (2H, d, J 8.5 Hz, 2H of C₆H₄CN or C₆H₄Cl), 7.75 (2H, d, J8.5 Hz, 2H of C₆H₄CN or C₆H₄Cl), 7.47 (2H, d, J 8.5 Hz, 2H of C₆H₄CN orC₆H₄Cl), 7.25 (1H, m, NH or 1×py), 4.26 (2H, s, CH ₂C₆H₄CN), 4.19 (1H,m, pipH-4 or BzpipH-4), 3.90 (2H, m, 2H of pip or Bzpip), 3.62 (2H, m,2H of pip or Bzpip), 3.45 (1H, m, pipH-4 or BzpipH-4), 3.07 (2H, m, 2Hof pip or Bzpip), 2.81 (2H, m, 2H of pip or Bzpip), 2.20-1.85 (8H, m, 4Hof pip, 4H of Bzpip); m/z: 542, 544 [M+H]⁺.

Compound 267:N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(1-(4-cyanophenyl)piperidin-4-ylamino)picolinamide.¹H nmr (CDCl₃) δ 7.99 (1H, d, J 8.5 Hz, pyH-3), 7.89 (1H, d, J 2.0 Hz,pyH-6), 7.65 (1H, d, J 8.5 Hz, NH), 7.66 (2H, d, J 9.0 Hz, 2H ofCH₂C₆H₄CN or NC₆H₄CN), 7.60 (2H, d, J 8.5 Hz, 2H of CH₂C₆H₄CN orNC₆H₄CN), 7.45 (2H, d, J 7.5 Hz, 2H of CH₂C₆H₄CN or NC₆H₄CN), 6.94 (1H,dd, J 9.0, 2.5 Hz, pyH-4), 6.89 (2H, d, J 9.0 Hz, 2H of CH₂C₆H₄CN orNC₆H₄CN), 3.99 (2H, m, 2H of pip), 3.85 (2H, m, 2H of pip), 3.60 (1H, m,1H of pip), 3.55 (2H, s, CH ₂C₆H₄CN), 3.08 (2H, t, J 11.5 Hz, 2H ofpip), 2.80 (2H, m, 2H of pip), 2.21 (4H, m, 4H of pip), 1.99 (2H, m, 2Hof pip), 1.59 (3H, m, 3H of pip); m/z: 520 [M+H]⁺.

Compound 268:N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(2-(4-fluorophenyl)propan-2-yl)piperazine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 8.57 (1H, m, pyH-6), 8.20 (1H, d, J 8.0 Hz, pyH-3),7.91 (1H, d, J 8.5 Hz, NH), 7.84 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.61(2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.49-7.29 (4H, m, 2H of C₆H₄CN, 2H ofC₆H₄F), 6.98 (2H, t, J 9.0 Hz, 2H of C₆H₄F), 4.00 (1H, m, pipH-4), 3.76(2H, m, 2H of piz), 3.56 (2H, s, CH ₂C₆H₄CN), 3.33 (2H, m, 2H of piz),2.81 (2H, m, 2H of pip), 2.57 (2H, m, 2H of piz), 2.40 (2H, m, 2H ofpiz), 2.22 (2H, dd, J 11.0, 9.5 Hz, 2H of pip), 2.01 (2H, m, 2H of pip),1.63 (2H, m, 2H of pip), 1.33 (6H, s, C(CH₃)₂); m/z: 569 [M+H]⁺.

Compound 269:N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(pyridin-4-yloxy)piperidine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 8.60 (1H, m, pyH-6), 8.44 (2H, d, J 6.0 Hz, 2H of Opy),8.24 (1H, d, J 8.0 Hz, pyH-3), 7.92 (1H, m, NH), 7.89 (1H, dd, J 8.0,2.0 Hz, pyH-4), 7.60 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.45 (2H, d, J 8.5Hz, 2H of C₆H₄CN), 6.81 (2H, d, J 6.5 Hz, 2H of Opy), 4.72 (1H, m,PyOpipH-4), 4.05-3.87 (3H, m, pipH-4, 2H of PyOpipH-2, H-6), 3.63 (1H,m, 1H of PyOpipH-2, H-6), 3.56 (2H, s, CH₂C₆H₄CN), 3.41 (1H, m, 1H ofPyOpipH-2, H-6), 2.81 (2H, m, 2H of pipH-2, H-6), 2.23 (2H, dd, J 11.0,10.0, 2H of pipH-2, H-6), 2.02 (2H, m, 2H of pipH-3, H-5), 2.00-1.79(4H, m, 4H of PyOpipH-3, H-5), 1.64 (2H, m, 2H of pipH-3, H-5); m/z: 525[M+H]⁺.

Compound 270:(S)—N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(3-(4-fluorophenoxy)pyrrolidine-1-carbonyl)picolinamide.¹H nmr (CDCl₃ @ 50° C.) δ 8.72 (1H, br s, pyH-6), 8.22 (1H, d, J 8.0 Hz,pyH-3), 7.98 (1H, m, NH or pyH-4), 7.90 (1H, d, J 8.0 Hz, NH or pyH-4),7.59 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.45 (2H, d, J 8.5 Hz, 2H ofC₆H₄CN), 6.97 (2H, m, 2H of C₆H₄F), 6.80 (2H, m, 2H of C₆H₄F), 4.90 (1H,m, pyrrolidineH-3), 4.01 (1H, m, pipH-4), 3.98-3.86 (2H, m, 1H ofpyrrolidineH-2, 1H of pyrrolidineH-5), 3.80-3.50 (2H, m, 1H ofpyrrolidineH-2, 1H of pyrrolidineH-5), 3.56 (2H, s, CH ₂C₆H₄CN), 2.80(2H, m, 2H of pipH-2, H-6), 2.29-2.14 (4H, m, 2H of pipH-2, H-6,pyrrolidineH-4), 2.02 (2H, m, 2H of pipH-3, H-5), 1.66 (2H, m, 2H ofpipH-3, H-5); ¹⁹F nmr (CDCl₃ @ 50° C.) δ −122.3; m/z: 528 [M+H]⁺.

Compound 271:N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(2,4-difluorobenzoyl)piperidine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 8.58 (1H, m, pyH-6), 8.23 (1H, d, J 8.0 Hz, pyH-3),7.94-7.84 (3H, m, NH, pyH-4, 1H of BzH-5 or BzH-6), 7.61 (2H, d, J 8.5Hz, 2H of C₆H₄CN), 7.45 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 6.99 (1H, m,BzH-5 or BzH-6), 6.89 (ddd, J 11.0, 8.5, 2.5 Hz, BzH-3), 4.65 (1H, m, 1Hof BzpipH-2, H-6), 4.00 (1H, m, pipH-4), 3.75 (1H, m, 1H of BzpipH-2,H-6), 3.56 (2H, s, CH ₂C₆H₄CN), 3.41 (1H, m, BzpipH-4), 3.20 (1H, m, 1Hof BzpipH-2, H-6), 3.07 (1H, m, 1H of BzpipH-2, H-6), 2.81 (2H, m, 2H ofpipH-2, H-6), 2.22 (2H, d, J 11.0, 10.0 Hz, 2H of pipH-2, H-6), 2.03(3H, m, 2H of pipH-3, H-5, 1H of BzpipH-3, H-5), 1.86 (1H, m, 1H ofBzpipH-3, H-5), 1.75-1.58 (4H, m, 2H of pipH-3, H-5, 2H of BzpipH-3,H-5); m/z: 572 [M+H]⁺.

Compound 272:5-(4-(4-fluorobenzoyl)piperidine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3-yl)picolinamide.¹H nmr (CDCl₃) δ 9.91 (1H, s, 1×NH or ArH), 8.68 (1H, m, 1×NH or ArH),8.42-8.33 (3H, m, NH, 2×ArH or 3×ArH), 8.01-7.95 (3H, m, NH, 2×ArH or3×ArH), 7.20-7.08 (5H, m, NH, 4×ArH or 5×ArH), 6.97 (2H, d, J 9.0 Hz,2×ArH), 4.67 (1H, m, 1H of BzpipH-2, H-4, H-6), 3.76 (1H, m, 1H ofBzpipH-2, H-4, H-6), 3.49 (1H, m, 1H of BzpipH-2, H-4, H-6), 3.26 (1H,m, 1H of BzpipH-2, H-4, H-6), 3.14 (1H, m, 1H of BzpipH-2, H-4, H-6),2.04 (1H, m, 1H of BzpipH-3, H-5), 1.84 (3H, m, 3H of BzpipH-3, H-5);m/z: 543 [M+H]⁺.

Compound 273:5-(4-(4-fluorophenoxy)piperidine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3-yl)picolinamide.¹H nmr (CDCl₃) δ 9.90 (1H, s, NH or 1×ArH), 8.68 (1H, m, 1×ArH),8.41-8.33 (3H, NH, 2×ArH or 3×ArH), 7.96 (1H, dd, J 8.0, 2.0 Hz, 1×ArH),7.11-7.08 (4H, m, NH, 3×ArH or 4×ArH), 7.02-6.95 (3H, NH, 2×ArH or3×ArH), 6.89-6.85 (2H, m, 2×ArH), 4.54 (1H, m, PhOpipH-4), 3.91 (2H, m,2H of PhOpipH-2, H-6), 3.66 (1H, m, 1H of PhOpipH-2, H-6), 3.39 (1H, m,1H of BzpipH-2, H-6), 2.00 (2H, m, 2H of PhOpipH-3, H-5), 1.86 (2H, m,2H of PhOpipH-3, H-5); m/z: 531 [M+H]⁺.

Compound 274:N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(3-(4-methoxyphenoxy)piperidine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 8.60 (1H, s, pyH-6), 8.23 and 8.11 (1H, 2m, pyH-3),7.87 (2H, m, NH, pyH-4), 7.61 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.45 (2H,d, J 8.0 Hz, 2H of C₆H₄CN), 6.92-6.73 (4H, m, 4H of C₆H₄OCH₃), 4.24 (2H,m, 1H of PhOpipH-2, H-6, PhOpipH-3), 3.99 (1H, m, pipH-4), 3.75 (3H, s,OCH₃), 3.67 (1H, m, 1H of PhOpipH-2, H-6), 3.56 (2H, s, CH ₂C₆H₄CN),3.43 (1H, m, 1H of PhOpipH-2, H-6), 3.29 (1H, m, 1H of PhOpipH-2, H-6),2.81 (2H, m, 2H of pipH-2, H-6), 2.22 (2H, t, J 11.0 Hz, 2H of pipH-2,H-6), 2.01 (4H, m, 2H of pipH-3, H-5, 2H of PhOpipH-4, H-5), 1.82 (1H,m, 1H of PhOpipH-4, H-5), 1.65 (3H, m, 2H of pipH-3, H-5, 1H ofPhOpipH-4, H-5); m/z: 555 [M+H]⁺.

Compound 275:N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(1-(4-methoxyphenyl)piperidin-4-ylamino)picolinamide.¹H nmr (CDCl₃) δ 7.98 (1H, d, J 8.5 Hz, pyH-3), 7.88 (1H, d, J 2.0 Hz,pyH-6), 7.68 (1H, d, J 8.5 Hz, NH), 7.61 (2H, d, J 8.5 Hz, 2H ofC₆H₄CN), 7.47 (2H, d, J 7.5 Hz, 2H of C₆H₄CN), 6.93 (3H, m, 2H ofC₆H₄OCH₃, pyH-4), 6.84 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 4.03-3.97 (2H,m, 2×pipH-4), 3.77 (3H, s, OCH₃), 3.58 (2H, s, CH ₂C₆H₄CN), 3.49 (4H, m,2×2H of pipH-2, H-6), 2.83 (4H, m, 2×2H of pipH-2, H-6), 2.28-2.15 (4H,m, 2×2H of pipH-3, H-5), 2.00 (2H, m, 2H of pipH-3, H-5), 1.66 (2H, m,2H of pipH-3, H-5); m/z: 525 [M+H]⁺.

Compound 276:N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(1-(4-fluorophenyl)piperidin-4-ylamino)picolinamide.¹H nmr (CDCl₃) δ 8.17 (1H, d, J 3.0 Hz, pyH-6), 8.02 (1H, d, J 8.5 Hz,pyH-3), 7.73 (1H, d, J 8.5 Hz, CONH), 7.61 (2H, d, J 8.0 Hz, 2H ofC₆H₄CN), 7.45 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.22 (1H, dd, J 9.0, 3.0Hz, pyH-4), 6.89 (2H, t, J 8.5 Hz, 2H of C₆H₄F), 6.56 (2H, dd, J 9.0,4.5 Hz, 2H of C₆H₄F), 3.98 (1H, m, pipH-4), 3.79 (2H, m, 2H of Phpip),3.55 (2H, s, CH ₂C₆H₄CN), 3.44 (1H, m, PhpipH-4), 3.04 (2H, m, 2H ofPhpip), 2.80 (2H, m, 2H of pipH-2, H-6), 2.21 (4H, m, 2H of Phpip, 2H ofpipH-2, H-6), 1.99 (2H, m, 2H of pipH-3, H-5), 1.76-1.47 (4H, m 2H ofpipH-3, H-5, 2H of Phpip); m/z: 513 [M+H]⁺.

Compound 277:N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(3-(3-methoxyphenoxy)piperidine-1-carbonyl)picolinamide.¹H nmr (CDCl₃ @ 50° C.) δ 8.58 (1H, s, pyH-6), 8.12 (1H, br s, pyH-3),7.87 (1H, d, J 8.5 Hz, NH), 7.83 (1H, m, pyH-4), 7.60 (2H, d, J 8.0 Hz,2H of C₆H₄CN), 7.45 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.12 (1H, t, J 7.5Hz, 1H of C₆ H ₄OCH₃), 6.49 (1H, d, J 8.5 Hz, 1H of C₆ H ₄OCH₃), 6.40(2H, m, 2H of C₆ H ₄OCH₃), 4.32 (1H, m, PhOpipH-3), 4.00 (1H, m,pipH-4), 3.76 (3H, s, OCH₃), 3.59 (1H, m, 1H of PhOpipH-2), 3.56 (2H, s,CH ₂C₆H₄CN), 3.37 (2H, m, PhOpipH-6), 2.80 (3H, m, 2H of pipH-2, H-6, 1Hof PhOpipH-2), 2.25 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 1.98 (4H, m,2H of pipH-3, H-5, 2H of PhOpipH-4, H-5), 1.71-1.59 (4H, m, 2H ofpipH-3, H-5, 2H of PhOpipH-4, H-5); m/z: 554 [M+H]⁺.

Compound 278:(R)—N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(3-(4-fluorophenoxy)pyrrolidine-1-carbonyl)picolinamide.¹H nmr (CDCl₃ @ 50° C.) δ 8.72 (1H, br s, pyH-6), 8.22 (1H, d, J 7.5 Hz,pyH-3 or H-4), 7.98 (1H, br s, NH), 7.90 (1H, d, J 8.0 Hz, pyH-3 orH-4), 7.59 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.45 (2H, d, J 8.5 Hz, 2H ofC₆H₄CN), 6.98 (2H, m, 2H of C₆H₄F), 6.90-6.78 (2H, m, 2H of C₆H₄F), 4.92(1H, m, pyrrolidineH-3), 4.01 (1H, m, pipH-4), 3.98-3.85 (2H, m, 1H ofpyrrolidineH-2, 1H of pyrrolidineH-5), 3.78-3.50 (2H, m, 1H ofpyrrolidineH-2, 1H of pyrrolidineH-5), 3.56 (2H, s, CH₂C₆H₄CN), 2.80(2H, m, 2H of pipH-2, H-6), 2.25 (2H, t, J 11.5 Hz, 2H of pipH-2, H-6),2.16 (2H, m, pyrrolidineH-4), 2.02 (2H, m, 2H of pipH-3, H-5), 1.65 (2H,m, 2H of pipH-3, H-5); m/z: 528 [M+H]⁺.

Compound 279:N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-((trans)-4-(4-cyanophenoxy)-3-fluoropiperidine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 8.62 (1H, m, pyH-6), 8.26 (1H, d, J 8.0 Hz, pyH-3),7.92 (2H, m, NH, pyH-4), 7.63 (2H, d, J 9.0 Hz, 2H of OC₆H₄CN), 7.61(2H, d, J 8.0 Hz, 2H of CH₂C₆ H ₄CN), 7.46 (2H, d, J 8.5 Hz, 2H of CH₂C₆H ₄CN), 7.01 (2H, d, J 9.0 Hz, 2H of OC₆H₄CN), 4.75 (1H, m, PhOpipH-4),4.75-4.03 (2H, m, 2H of PhOpipH-2, H-3, H-6), 4.01 (1H, m, pipH-4), 3.78(1H, m, 1H of PhOpipH-2, H-3, H-6), 3.68-3.37 (2H, m, 2H of PhOpipH-2,H-3, H-6), 3.57 (2H, s, CH ₂C₆H₄CN), 2.82 (2H, m, 2H of pipH-2, H-6),2.23 (2H, dd, J 11.0, 10.0 Hz, 2H of pipH-2, H-6), 2.02 (2H, m, 2H ofpipH-3, H-5), 1.63 (4H, m, 2H of pipH-3, H-5, 2H of PhOpipH-6); m/z: 567[M+H]⁺.

Compound 280:N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-((1R,3r,5S)-3-(4-cyanophenoxy)-8-azabicyclo[3.2.1]octane-8-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 8.69 (1H, d, J 1.5 Hz, pyH-6), 8.25 (1H, d, J 8.0 Hz,pyH-3), 7.97 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.92 (1H, d, J 8.5 Hz, NH),7.61 (2H, d, J 8.5 Hz, 2H of CH₂C₆ H ₄CN), 7.57 (2H, d, J 9.0 Hz, 2H ofOC₆H₄CN), 7.45 (2H, d, J 8.0 Hz, 2H of CH₂C₆ H ₄CN), 6.93 (2H, d, J 9.0Hz, 2H of OC₆H₄CN), 4.67 (1H, m, 1H of PhOpipH-2, H-4, H-6), 4.82 (1H,m, 1H of PhOpipH-2, H-4, H-6), 4.13 (1H, m 1H of PhOpipH-2, H-4, H-6),4.01 (1H, m pipH-4), 3.56 (2H, s, CH ₂C₆H₄CN), 2.81 (2H, m, 2H ofpipH-2, H-6), 2.22 (2H, t, J 11.5 Hz, pipH-2, H-6), 2.17 (4H, m, 4H ofPhOpip), 2.01 (2H, m, 2H of pipH-3, H-5), 1.86 (2H, d, J 7.5 Hz, 2H ofPhOpip), 1.68 (4H, m, 2H of pipH-3, H-5, 2H of PhOpip); m/z: 575 [M+H]⁺.

Compound 281:N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(3,4-difluorobenzoyl)piperidine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 8.59 (1H, m, pyH-6), 8.23 (1H, d, J 8.0 Hz, pyH-3),7.94-7.84 (3H, NH, pyH-4, BzH-5 or H-6), 7.61 (2H, d, J 8.5 Hz, 2H ofC₆H₄CN), 7.46 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 6.99 (1H, m, BzH-5 orH-6), 6.89 (1H, ddd, J 11.0, 9.0, 2.0 Hz, BzH-2), 4.63 (1H, m, 1H ofBzpipH-2, H-6), 4.01 (1H, m, pipH-4), 3.71 (1H, m, 1H of BzpipH-2, H-6),3.56 (2H, s, CH ₂C₆H₄CN), 3.41 (1H, m, BzpipH-4), 3.20 (1H, m 1H ofBzpipH-2, H-6), 3.08 (1H, m, BzpipH-2, H-6), 2.81 (2H, m, 2H of pipH-2,H-6), 2.23 (2H, dd, 11.5, 10.0 Hz, pipH-2, H-6), 2.12-1.82 (4H, m, 2H ofpipH-3, H-5, 2H of BzpipH-3, H-5), 1.78-1.59 (4H, m, 2H of pipH-3, H-5,2H of BzpipH-3, H-5); m/z: 572 [M+H]⁺.

Compound 282:N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(2,4-difluorophenoxy)piperidine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 8.60 (1H, m, pyH-6), 8.25 (1H, d, J 8.0 Hz, pyH-3),7.92 (1H, d, J 9.0 Hz, NH), 7.89 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.61(2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.46 (2H, d, J 8.5 Hz, 2H of C₆H₄CN),6.98 (1H, td, J 9.0, 5.5 Hz, PhH-5), 6.87 (1H, ddd, J 11.0, 8.5, 3.0 Hz,PhH-2), 6.80 (1H, m, PhH-6), 4.47 (1H, m, PhOpipH-4), 4.00 (1H, m,pipH-4), 3.90 (2H, m, 2H of PhOpipH-2, H-6), 3.68 (1H, m, 1H ofPhOpipH-2, H-6), 3.56 (2H, s, CH ₂C₆H₄CN), 3.49 (1H, m, 1H of PhOpipH-2,H-6), 2.82 (2H, m, 2H of pipH-2, H-6), 2.23 (2H, t, J 11.0 Hz, 2H ofpipH-2, H-6), 2.03-1.96 (4H, m, 2H of pipH-3, H-5, 2H of PhOpipH-3,H-5), 1.85 (2H, m, 2H of PhOpipH-3, H-5), 1.65 (2H, m, 2H of pipH-3,H-5); m/z: 560 [M+H]⁺.

Compound 283:N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(pyridin-3-yloxy)piperidine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 8.61 (1H, m, pyH-6), 8.33 (1H, m, OpyH-2), 8.26-8.23(2H, m, pyH-3, 1H of OpyH), 7.92 (1H, d, J 9.5 Hz, NH), 7.89 (1H, dd, J8.5, 2.0 Hz, pyH-4), 7.61 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.45 (2H, d,J 8.0 Hz, 2H of C₆H₄CN), 7.23 (2H, m, 2H of OpyH), 4.66 (1H, mpyOpipH-4), 4.01 (1H, m, pipH-4), 3.91 (2H, m, 2H of pyOpipH-2, H-6),3.66 (1H, m, 1H of pyOpipH-2, H-6), 3.40 (1H, m, 1H of pyOpipH-2, H-6),2.81 (2H, m, 2H of pipH-2, H-6), 2.22 (2H, dd, J 11.0, 10.0 Hz, 2H ofpipH-2, H-6), 2.04-1.88 (6H, m, 2H of pipH-3, H-5, 4H of pyOpipH-3,H-5), 3.56 (2H, s, CH₂C₆H₄CN), 1.64 (2H, m, 2H of pipH-3, H-5); m/z: 525[M+H]⁺.

Compound 284: ethyl4-(1-(6-(1-(4-cyanobenzyl)piperidin-4-ylcarbamoyl)nicotinoyl)piperidin-4-yloxy)benzoate.¹H nmr (CDCl₃) δ 8.60 (1H, m, pyH-6), 8.24 (1H, d, J 8.0 Hz, pyH-3),7.99 (2H, d, J 8.5 Hz, 2H of C₆H₄CO₂Et), 7.92 (1H, d, J 9.5 Hz, NH),7.89 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.61 (2H, d, J 8.5 Hz, 2H ofC₆H₄CN), 7.46 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 6.92 (2H, d, J 9.0 Hz, 2Hof C₆H₄CO₂Et), 4.72 (1H, m, PhOpipH-4), 4.34 (2H, q, J 7.0 Hz, OCH₂CH₃),4.02-3.87 (3H, m, pipH-4, 2H of PhOpipH-2, H-6), 3.64 (1H, m, 1H ofPhOpipH-2, H-6), 3.57 (2H, s, CH ₂C₆H₄CN), 3.55 (1H, m, 1H of PhOpipH-2,H-6), 2.83 (2H, m, 2H of pipH-2, H-6), 2.24 (2H, t, J 10.5 Hz, pipH-2,H-6), 2.03-1.88 (6H, m, pipH-3, H-5, 4H of PhOpipH-3, H-5), 1.67 (2H, m,2H of pipH-3, H-5), 1.37 (3H, t, J 7.0 Hz, OCH₂CH ₃); m/z: 597 [M+H]⁺.

Compound 285:5-(4-(4-cyanobenzyl)piperazine-1-carbonyl)-N-(1-(4-methoxybenzyl)piperidin-4-yl)picolinamide.¹H nmr (CDCl₃) δ 8.58 (1H, m, pyH-6), 8.22 (1H, d, J 8.0 Hz, pyH-3),7.90 (1H, d, J 9.0 Hz, NH), 7.86 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.62(2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.45 (2H, d, J 8.0 Hz, 2H of C₆H₄CN),7.25 (2H, d, J 8.0 Hz, 2H of C₆H₄OCH₃), 6.86 (2H, d, J 8.5 Hz, 2H ofC₆H₄OCH₃), 4.00 (1H, m, pipH-4), 3.80 (5H, m, 2H of piz, OCH₃), 3.59(2H, s, 1×CH₂Ar), 3.52 (2H, s, 1×CH₂Ar), 3.41 (2H, m, 2H of piz), 2.90(2H, m, 2H of pipH-2, H-6), 2.54 (2H, m, 2H of piz), 2.41 (2H, m, 2H ofpiz), 2.22 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 2.01 (2H, m, 2H ofpipH-3, H-5), 1.67 (2H, m, 2H of pipH-3, H-5); m/z: 553 [M+H]⁺.

Compound 286:5-(4-(4-cyano-2-methoxyphenoxy)piperidin-1-yl)-N-(1-(4-cyanobenzyl)piperidin-4-yl)picolinamide.¹H nmr (CDCl₃) δ 8.18 (1H, d, J 2.5 Hz, pyH-6), 8.02 (1H, d, J 9.0 Hz,pyH-3), 7.73 (1H, d, 8.5 Hz, CONH), 7.61 (2H, d, J 8.5 Hz, 2H ofC₆H₄CN), 7.46 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.26-7.21 (2H, m, pyH-4,C₆H₃(OCH₃)CNH-5), 7.11 (1H, d, J 1.5 Hz, C₆H₃(OCH₃)CNH-3), 6.95 (1H, d,J 8.5 Hz, C₆H₃(OCH₃)CNH-6), 4.60 (1H, m, PhOpipH-4), 3.99 (1H, m,pipH-4), 3.86 (3H, s, OCH₃), 3.69-3.61 (4H, m, 2H of PhOpipH-2, H-6, CH₂C₆H₄CN), 3.30 (2H, m, 2H of PhOpipH-2, H-6), 2.84 (2H, m, 2H of pipH-2,H-6), 2.26 (2H, dd, J 11.0, 10.0 Hz, 2H of pipH-2, H-6), 2.14-1.96 (6H,m, 2H of pipH-3, H-5, 4H of PhOpipH-3, H-5), 1.65 (2H, m, 2H of pipH-3,H-5); m/z: 552 [M+H]⁺.

Compound 287:N-(1-(3,5-difluorobenzyl)piperidin-4-yl)-5-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 8.60 (1H, d, J 2.0 Hz, pyH-6), 8.23 (1H, d, J 8.0 Hz,pyH-3), 7.94 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 7.92 (1H, m, NH), 7.89(1H, dd, J 8.0, 2.0 Hz, pyH-4), 6.95 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃),6.88 (2H, d, J 6.0 Hz, C₆H₃F₂H-2, H-6), 6.68 (1H, tt, J 9.0, 2.0 Hz,C₆H₃F₂H-4), 4.67 (1H, m, 1H of BzpipH-2, H-6), 4.01 (1H, m, pipH-4),3.87 (3H, s, OCH₃), 3.77 (1H, m, 1H of BzpipH-2, H-6), 3.54 (1H, m,BzpipH-4), 3.49 (2H, s, CH ₂C₆H₃F₂), 3.17 (2H, m, 2H of BzpipH-2, H-6),2.83 (2H, m, 2H of pipH-2, H-6), 2.23 (2H, dd, J 11.0, 9.5 Hz, 2H ofpipH-2, H-6), 2.02 (3H, m, 2H of pipH-3, H-5, 1H of BzpipH-3, H-5), 1.83(3H, m, 3H of BzpipH-3, H-5), 1.66 (2H, m, 2H of pipH-3, H-5); m/z: 577[M+H]⁺.

Compound 288:N-(1-(3,5-difluorobenzyl)piperidin-4-yl)-5-(4-(4-fluorobenzoyl)piperidine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 8.54 (1H, m, pyH-6), 8.17 (1H, d, J 8.0 Hz, pyH-3),7.91 (2H, dd, J 9.0, 5.0 Hz, 2H of C₆H₄F), 7.87 (1H, m, NH), 7.82 (1H,dd, J 8.0, 2.0 Hz, pyH-4), 7.10 (2H, t, J 8.5 Hz, 2H of C₆H₄F), 6.82(2H, d, J 6.5 Hz, C₆H₃F₂H-2 and H-6), 6.62 (1H, tt, J 9.0, 2.0 Hz,C₆H₃F₂H-4), 4.60 (1H, m, 1H of BzpipH-2, H-6), 4.00 (1H, m, pipH-4),3.69 (1H, m, 1H of BzpipH-2, H-6), 3.47 (1H, m, BzpipH-4), 3.44 (2H, s,CH₂C₆H₃F₂), 3.11 (2H, m, 2H of BzpipH-2, H-6), 2.78 (2H, m, 2H ofpipH-2, H-6), 2.17 (2H, dd, J 11.0, 9.5 Hz, 2H of pipH-2, H-6), 1.95(2H, m, 2H of pipH-3, H-5), 1.76 (4H, m, 4H of BzpipH-3, H-5), 1.60 (2H,m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −104.4, −110.5; m/z: 565[M+H]⁺.

Compound 289:5-(4-(4-cyanophenoxy)piperidine-1-carbonyl)-N-(1-(3,5-difluorobenzyl)piperidin-4-yl)picolinamide.¹H nmr (CDCl₃) δ 8.60 (1H, m, pyH-6), 8.24 (1H, d, J 8.0 Hz, pyH-3),7.91 (1H, d, J 8.0 Hz, NH), 7.89 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.59(2H, d, J 9.0 Hz, 2H of C₆H₄CN), 9.69 (2H, d, J 9.0 Hz, 2H of C₆H₄CN),6.87 (2H, d, J 8.0 Hz, C₆H₃F₂H-2, H-6), 6.68 (1H, m, C₆H₃F₂H-4), 4.70(1H, m, PhOpipH-4), 4.00 (1H, m, pipH-4), 3.89 (2H, m, 2H of PhOpipH-2,H-6), 3.65 (1H, m, 1H of PhOpipH-2, H-6), 3.49 (2H, s, CH ₂C₆H₃F₂), 3.41(1H, m, 1H of PhOpipH-2, H-6), 2.83 (2H, m, 2H of pipH-2, H-6), 2.22(2H, t, J 11.5 Hz, 2H of pipH-2, H-6), 2.03-1.1.83 (6H, m, 2H of pipH-3,H-5, 4H of PhOpipH-3, H-5), 1.65 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr(CDCl₃) δ −110.5; m/z: 560 [M+H]⁺.

Compound 290: tert-butyl3-(2-(1-(4-cyanobenzyl)piperidin-4-ylcarbamoyl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)pyridin-3-yl)propylcarbamate.¹H nmr (CDCl₃) δ 8.42 (1H, d, J 1.5 Hz, pyH-6), 8.03 (1H, d, J 8.5 Hz,PyCONH), 7.61 (3H, m, pyH-4, 2H of C₆H₄CN), 7.45 (2H, d, J 8.5 Hz, 2H ofC₆H₄CN), 7.27 (2H, dd, J 8.6, 6.0 Hz, 2H of C₆H₄F), 7.01 (2H, t, J 8.5Hz, 2H of C₆H₄F), 5.02 (1H, m, NHCO₂), 3.93 (1H, m, pipH-4), 3.79 (2H,m, 2H of piz), 3.56 (2H, s, CH ₂C₆H₄CN or CH ₂C₆H₄F), 3.50 (2H, s, CH₂C₆H₄CN or CH ₂C₆H₄F), 3.40 (2H, m, 2H of piz), 3.17 (4H, m, PyCH ₂CH₂CH₂NH), 2.81 (2H, m, 2H of pipH-2, H-6), 2.79 (2H, m, 2H of piz), 2.53(2H, m, 2H of piz), 2.21 (2H, t, J 10.5 Hz, 2H of pipH-2, H-6), 2.00(2H, m, 2H of pipH-3, H-5), 1.84 (2H, m, PyCH₂CH₂CH₂NH), 1.66 (2H, m, 2Hof pipH-3, H-5), 1.43 (9H, s, C(CH₃)₃); m/z: 699 [M+H]⁺.

Compound 291:N-(1-(4-cyanobenzyl)piperidin-4-yl)-3-(5,21-dioxo-25-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-8,11,14,17-tetraoxa-4,20-diazapentacosyl)-5-(4-(4-fluorobenzyl)piperazine-1-carbonyl)picolinamide(as its trifluoroacetate salt). m/z: 1072 [M+H]⁺.

Compound 292:N-(1-(3,5-difluorobenzyl)piperidin-4-yl)-5-(S)-3-(4-fluorophenoxy)pyrrolidine-1-carbonyl)picolinamide.m/z: 539 [M+H]⁺ (found [M+H]⁺, 539.2314, C₂₉H₂₉F₃N₄O₃ requires [M+H]⁺539.2265).

Compound 293:N-(1-(3,5-difluorobenzyl)piperidin-4-yl)-5-(4-(p-tolyloxy)piperidine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 8.60 (1H, m, pyH-6), 8.24 (1H, d, J 8.0 Hz, pyH-3),7.93 (1H, d, J 8.5 Hz, NH), 7.88 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.09(2H, d, J 9.0 Hz, 2H of C₆H₄CH₃), 6.88 (2H, d, J 6.5 Hz, C₆H₃F₂H-2,H-6), 6.82 (2H, d, J 8.5 Hz, 2H of C₆H₄CH₃), 6.80 (1H, tt, J 9.0, 2.0Hz, C₆H₃F₂H-4), 4.56 (1H, m, PhOpipH-4), 4.01 (1H, m, pipH-4), 3.89 (2H,m, 2H of PhOpipH-2, H-6), 3.64 (1H, m, 1H of PhOpipH-2, H-6), 3.49 (2H,s, CH₂C₆H₃F₂), 2.83 (2H, m, 2H of pipH-2, H-6), 2.29 (3H, s, ArCH3),2.22 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 2.04-1.84 (6H, m, 2H ofpipH-3, H-5, PhOpipH-3, H-5), 1.68 (2H, m, 2H of pipH-3, H-5); m/z: 550[M+H]⁺.

Compound 294:N-(1-(3,5-difluorobenzyl)piperidin-4-yl)-5-(4-(4-(trifluoromethyl)phenoxy)piperidine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 8.61 (1H, m, pyH-6), 8.24 (1H, d, J 8.0 Hz, pyH-3),7.93 (1H, m, NH), 7.88 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.55 (2H, d, J8.5 Hz, 2H of C₆H₄CF₃), 6.98 (2H, d, J 8.5 Hz, 2H of C₆H₄CF₃), 6.88 (2H,d, J 6.0 Hz, C₆H₃F₂H-2, H-6), 6.68 (1H, tt, J 9.0, 2.0 Hz, C₆H₃F₂H-4),4.70 (1H, m, PhOpipH-4), 4.01 (1H, m, pipH-4), 3.87 (2H, m, 2H ofPhOpipH-2, H-6), 3.65 (1H, m, 1H of PhOpipH-2, H-6), 3.49 (2H, s, CH₂C₆H₃F₂), 3.35 (1H, m, 1H of PhOpipH-2, H-6), 2.82 (2H, m, 2H of pipH-2,H-6), 2.22 (2H, dd, J 11.5, 10.0 Hz, 2H of pipH-2, H-6), 2.12-1.84 (6H,m, 2H of pipH-3, H-5, PhOpipH-3, H-5), 1.65 (2H, m, 2H of pipH-3, H-5);m/z: 603 [M+H]⁺.

Compound 295:N-(1-(3,5-difluorobenzyl)piperidin-4-yl)-5-(4-(4-fluorophenoxy)piperidine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 8.60 (1H, m, pyH-6), 8.28 (1H, d, J 8.0 Hz, pyH-3),7.92 (1H, m, NH), 7.88 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 6.98 (2H, t, J8.0 Hz, 2H of C₆H₄F), 6.89-6.84 (4H, m, 2H of C₆H₄F, C₆H₃F₂H-2, H-6),6.68 (1H, br t, J 8.5 Hz, C₆H₃F₂H-4), 4.52 (1H, m, PhOpipH-4), 4.01 (1H,m, pipH-4), 3.89 (2H, m, 2H of PhOpipH-2, H-6), 3.64 (1H, m, 1H ofPhOpipH-2, H-6), 3.49 (2H, s, CH₂C₆H₃F₂), 3.36 (1H, m, 1H of PhOpipH-2,H-6), 2.83 (2H, m, 2H of pipH-2, H-6), 2.22 (2H, t, J 11.0 Hz, 2H ofpipH-2, H-6), 2.04-1.85 (6H, m, 2H of pipH-3, H-5, PhOpipH-3, H-5), 1.64(2H, m, 2H of pipH-3, H-5); m/z: 525 [M+H]⁺.

Compound 296:N-(1-(3,5-difluorobenzyl)piperidin-4-yl)-5-(4-(4-methoxyphenoxy)piperidine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 8.60 (1H, m, pyH-6), 8.24 (1H, d, J 8.0 Hz, pyH-3),7.93 (1H, d, J 8.0 Hz, NH), 7.88 (1H, dd, J 8.0, 2.0 Hz, pyH-4),6.90-6.82 (6H, m, C₆H₄OCH₃, C₆H₃F₂H-2, H-6), 6.69 (1H, tt, J 9.0, 2.0Hz, C₆H₃F₂H-4), 4.47 (1H, m, PhOpipH-4), 4.01 (1H, m, pipH-4), 3.89 (2H,m, 2H of PhOpipH-2, H-6), 3.77 (3H, s, OCH₃), 3.64 (1H, m, 1H ofPhOpipH-2, H-6), 3.50 (2H, s, CH₂C₆H₃F₂), 3.35 (1H, m, 1H of PhOpipH-2,H-6), 2.84 (2H, m, 2H of pipH-2, H-6), 2.24 (2H, t, J 11.0 Hz, 2H ofpipH-2, H-6), 2.04-1.83 (6H, m, 2H of pipH-3, H-5, PhOpipH-3, H-5), 1.66(2H, m, 2H of pipH-3, H-5); m/z: 565 [M+H]⁺ (found [M+H]⁺, 565.2657,C₃₁H₃₄F₂N₄O₄ requires [M+H]⁺ 565.2621).

Compound 297:N-(1-(3,5-difluorobenzyl)piperidin-4-yl)-5-(4-(3,4-difluorophenoxy)piperidine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 8.60 (1H, m, pyH-6), 8.24 (1H, d, J 8.0 Hz, pyH-3),7.94 (1H, d, J 8.5 Hz, NH), 7.89 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.07(1H, q, J 9.5 Hz, 1H of COC₆H₃F₂), 6.91 (2H, d, J 6.0 Hz, C₆H₃F₂H-2,H-6), 6.78-6.17 (2H, m, 2H of COC₆H₃F₂), 6.62 (1H, m, C₆H₃F₂H-4), 4.51(1H, m, PhOpipH-4), 4.04 (1H, m, pipH-4), 3.88 (2H, m, 2H of PhOpipH-2,H-6), 3.61 (3H, m, CH₂C₆H₃F₂, 1H of PhOpipH-2, H-6), 3.37 (1H, m, 1H ofPhOpipH-2, H-6), 2.95 (2H, m, 2H of pipH-2, H-6), 2.33 (2H, m, 2H ofpipH-2, H-6), 2.08-1.76 (8H, m, pipH-3, H-5, PhOpipH-3, H-5); ¹⁹F nmr(CDCl₃) δ −75.8, −134.9, −146.9; m/z: 571 [M+H]⁺(found [M+H]⁺, 571.2402,C₃₀H₃₀F₄N₄O₃ requires [M+H]⁺ 571.2327).

Compound 298:5-(4-(3,4-difluorobenzoyl)piperidine-1-carbonyl)-N-(1-(3,5-difluorobenzyl)piperidin-4-yl)picolinamide.¹H nmr (CDCl₃) δ 8.59 (1H, m, pyH-6), 8.23 (1H, d, J 8.0 Hz, pyH-3),7.96 (1H, d, J 8.5 Hz, NH), 7.93-7.85 (2H, m, pyH-4, COC₆H₃F₂H-5 orH-6), 6.99 (1H, td, J 7.5, 2.0 Hz, COC₆H₃F₂H-5 or H-6), 6.91-6.85 (3H,m, COC₆H₃F₂H-2, CH₂C₆H₃F₂H-2, H-6), 6.72 (1H, br t, J 9.0 Hz,CH₂C₆H₃F₂H-4), 4.65 (1H, m, 1H of BzpipH-2, H-6), 4.04 (1H, m, pipH-4),3.70 (1H, m, 1H of BzpipH-2, H-6), 3.61 (2H, s, CH₂C₆H₃F₂), 3.41 (1H, m,BzpipH-4), 3.21 (1H, m, BzpipH-2, H-6), 3.07 (1H, m, BzpipH-2, H-6),2.95 (2H, m, 2H of pipH-2, H-6), 2.33 (2H, m, 2H of pipH-2, H-6), 2.04(3H, m, 2H of pipH-3, H-5, 1H of BzpipH-3, H-5), 1.88 (1H, m, 1H ofBzpipH-3, H-5), 1.74 (4H, m, 2H of pipH-3, H-5, 2H of BzpipH-3, H-5);¹⁹F nmr (CDCl₃) δ −75.8, −101.2, −106.5; m/z: 583 [M+H]⁺ (found [M+H]⁺,583.2365, C₃₂H₃₄F₂N₄O₄ requires [M+H]⁺ 583.2327).

Compound 299:N-((cis)-4-(3,5-difluorophenoxy)cyclohexyl)-5-(4-(4-fluorophenoxy)piperidine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 8.60 (1H, m, pyH-6), 8.25 (1H, d, J 8.5 Hz, pyH-3),8.00 (1H, d, J 8.5 Hz, NH), 7.89 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 6.98(2H, dd, J 9.0, 8.0 Hz, 2H of C₆H₄F), 6.86 (2H, dd, J 9.5, 4.5 Hz, 2H ofC₆H₄F), 6.45-6.35 (3H, m, C₆H₃F₂), 4.52 (1H, m, 1H of cyHexH-1 orcyHexH-4 or PhOpipH-4), 4.46 (1H, m, 1H of cyHexH-1 or cyHexH-4 orPhOpipH-4), 4.09 (1H, m, 1H of cyHexH-1 or cyHexH-4 or PhOpipH-4), 3.89(2H, m 2H of PhOpipH-2, H-6), 3.64 (1H, m, PhOpipH-2, H-6), 3.36 (1H, m,PhOpipH-2, H-6), 2.08-1.75 (12H, m, cyHexH-2, H-3, H-5, H-6 andPhOpipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −109.4, −122.5; m/z: 525 [M+H]⁺.

Compound 300:N-((cis)-4-(3,5-difluorophenoxy)cyclohexyl)-5-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 8.60 (1H, m, pyH-6), 8.24 (1H, d, J 8.5 Hz, pyH-3),8.00 (1H, d, J 8.5 Hz, NH), 7.93 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 7.89(1H, dd, J 8.0, 2.0 Hz, pyH-4), 6.95 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃),6.45-6.35 (3H, m, C₆H₃F₂), 4.65 (1H, m, 1H of BzpipH-2, H-6), 4.46 (1H,m, cyHexH-1 or H-4), 4.09 (1H, m, cyHexH-1 or H-4), 3.87 (3H, s, OCH₃),3.77 (1H, m, 1H of BzpipH-2, H-6), 3.53 (1H, m, BzpipH-4), 3.16 (2H, m,2H of BzpipH-2, H-6), 2.08-2.03 (3H, m, 3H of cyHexH-2, H-3, H-5, H-6and BzpipH-3, H-5), 1.89-1.71 (9H, m, 9H of cyHexH-2, H-3, H-5, H-6 andBzpipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −109.4; m/z: 578 [M+H]⁺.

Compound 301:N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)picolinamide.¹H nmr (CDCl₃) δ 8.19 (1H, d, J 3.0 Hz, pyH-6), 8.01 (1H, d, J 8.5 Hz,pyH-3), 7.78 (1H, d, J 8.5 Hz, NH), 7.64 (2H, d, J 8.5 Hz, 2H ofC₆H₄CN), 7.55 (2H, d, J 9.0 Hz, 2H of C₆H₄CF₃), 7.50 (2H, d, J 8.5 Hz,2H of C₆H₄CN), 7.23 (1H, dd, J 9.0, 3.0 Hz, pyH-4), 6.98 (2H, d, J 9.0Hz, 2H of C₆H₄CF₃), 4.62 (1H, heptet, J 3.0 Hz, PhOpipH-4), 4.04 (1H, m,pipH-4), 3.78 (2H, s, CH ₂C₆H₄CN), 3.59 (2H, ddd, J 12.5, 8.5, 4.0 Hz,2H of PhOpipH-2, H-6), 3.34 (2H, ddd, J 12.5, 7.0, 3.5 Hz, 2H ofPhOpipH-2, H-6), 3.00 (2H, m, 2H of pipH-2, H-6), 2.43 (2H, m, 2H ofpipH-2, H-6), 2.14-1.92 (6H, m, PhOpipH-3, H-5, 2H of pipH-3, H-5), 1.77(2H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −61.6; m/z: 564[M+H]⁺(found [M+H]⁺, 564.2539, C₃₁H₃₂F₃N₅O₂ requires [M+H]⁺ 564.2581).

Compound 302:N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-methoxybenzoyl)piperidin-1-yl)picolinamide.¹H nmr (CDCl₃) δ 8.17 (1H, d, J 2.5 Hz, pyH-6), 7.99 (1H, d, J 9.0 Hz,pyH-3), 7.95 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 7.79 (1H, d, J 8.5 Hz,NH), 7.66 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.52 (2H, d, J 8.5 Hz, 2H ofC₆H₄CN), 7.22 (1H, dd, J 9.0, 2.5 Hz, pyH-4), 6.96 (2H, d, J 9.0 Hz, 2Hof C₆H₄OCH₃), 4.07 (1H, m, pipH-4), 3.94-3.81 (7H, m, 2H of BzpipH-2,H-6, OCH₃, CH ₂C₆H₄CN), 3.45 (1H, m, BzpipH-4), 3.13 (2H, m, 2H ofBzpipH-2, H-6 or 2H of pipH-2, H-6), 3.05 (2H, m, 2H of BzpipH-2, H-6 or2H of pipH-2, H-6), 2.52 (2H, m, 2H of pipH-2, H-6), 2.10 (2H, m, 2H ofpipH-3, H-5), 1.97 (4H, m, BzpipH-3, H-5), 1.91 (2H, m, 2H of pipH-3,H-5); m/z: 538 [M+H]⁺ (found [M+H]⁺, 538.2831, C₃₂H₃₅N₅O₃ requires[M+H]⁺ 538.2813).

Compound 303:5-(4-(4-cyanophenoxy)piperidine-1-carbonyl)-N-((cis)-4-(4-fluorophenoxy)cyclohexyl)picolinamide.¹H nmr (CDCl₃) δ 8.61 (1H, m, pyH-6), 8.26 (1H, d, J 8.0 Hz, pyH-3),8.01 (1H, d, J 8.5 Hz, NH), 7.89 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.60(2H, d, J 9.0 Hz, 2H of C₆H₄OCN), 7.00-6.94 (4H, m, 2H of C₆H₄CN, 2H ofC₆H₄F), 6.86 (2H, dd, J 9.0, 4.5 Hz, 2H of C₆H₄F), 4.70 (1H, m,PhOpipH-4), 4.42 (1H, m, cHexH-1), 4.09 (1H, m, cHexH-4), 3.88 (2H, m,2H of PhOpipH-2, H-6), 3.65 (1H, m, 1H of PhOpipH-2, H-6), 3.41 (1H, m,1H of PhOpipH-2, H-6), 2.06-2.00 (4H, m, 2H of PhOpipH-2, H-6, 2H ofcHexH-2, H-3, H-5, H-6), 1.87-1.75 (8H, 2H of PhOpipH-3, H-5, 6H ofcHexH-2, H-3, H-5, H-6); ¹⁹F nmr (CDCl₃) δ −123.5; m/z: 553 [M+H]⁺(found[M+H]⁺, 543.2429, C₃₁H₃₁FN₄O₄ requires [M+H]⁺ 543.2402).

Compound 304:5-(4-(4-fluorobenzoyl)piperidine-1-carbonyl)-N-((cis)-4-(4-fluorophenoxy)cyclohexyl)picolinamide.¹H nmr (CDCl₃) δ 8.61 (1H, m, pyH-6), 8.25 (1H, d, J 8.0 Hz, pyH-3),8.01 (1H, m, NH), 7.99 (2H, m, 2H of COC₆H₄F), 7.89 (1H, dd, J 8.0, 2.0Hz, pyH-4), 7.16 (2H, t, J 9.0 Hz, 2H of COC₆H₄F), 6.97 (2H, t, J 9.0Hz, 2H of OC₆H₄F), 6.87 (2H, dd, J 9.0, 4.5 Hz, 2H of OC₆H₄F), 4.66 (1H,m, 1H of BzpipH-2, H-6), 4.42 (1H, m, cHexH-1), 4.09 (1H, m, cHexH-4),3.76 (1H, m, 1H of BzpipH-2, H-6), 3.54 (1H, m, BzpipH-4), 2.04 (2H, m,2H of cHexH-2, H-6), 1.88-1.75 (10H, m, BzpipH-3, H-5, 6H of cHexH-2,H-3, H-5, H-6); ¹⁹F nmr (CDCl₃) δ −104.4, −123.6; m/z: 548 [M+H]⁺ (found[M+H]⁺, 548.2418, C₃₁H₃₁F₂N₃O₄ requires [M+H]⁺ 548.2356).

Compound 305:N-(2-(4-fluorophenoxy)ethyl)-5-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 8.62 (1H, m, pyH-6), 8.40 (1H, t, J 6.0 Hz, NH), 8.25(1H, d, J 8.0 Hz, pyH-3), 7.94 (2H, d, J 8.5 Hz, 2H of C₆H₄OCH₃), 7.90(1H, dd, J 8.0, 1.5 Hz, pyH-4), 7.00-6.91 (4H, m, 2H of C₆H₄OCH₃, 2H ofC₆H₄F), 6.87 (2H, dd, J 9.0, 4.5 Hz, 2H of C₆H₄F), 4.66 (1H, m, 1H ofBzpipH-2, H-6), 4.12 (2H, t, J 5.0 Hz, CH ₂OC₆H₄F), 3.88 (2H, q, J 5.5Hz, NHCH ₂), 3.74 (1H, m, BzpipH-2, H-6), 3.53 (1H, pentet, J 7.0 Hz,BzpipH-4), 3.15 (2H, m, 2H of BzpipH-2, H-6), 2.01 (1H, m, 1H ofBzpipH-3, H-5), 1.89-1.82 (3H, m, 3H of BzpipH-3, H-5); ¹⁹F nmr (CDCl₃)δ −123.6; m/z: 506 [M+H]⁺.

Compound 306:5-(4-(4-cyanophenoxy)piperidine-1-carbonyl)-N-(2-(4-fluorophenoxy)ethyl)picolinamide.¹H nmr (CDCl₃) δ 8.62 (1H, m, pyH-6), 3.39 (1H, t, J 6.0 Hz, NH), 8.26(1H, d, J 7.5 Hz, pyH-3), 7.90 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.60 (2H,d, J 9.0 Hz, 2H of C₆H₄CN), 7.00-6.95 (4H, m, 2H of C₆H₄CN, 2H ofC₆H₄F), 6.87 (2H, dd, J 9.0, 4.5 Hz, 2H of C₆H₄F), 4.70 (1H, m,PhOpipH-4), 4.13 (2H, t, J 5.0 Hz, CH ₂OC₆H₄F), 3.89 (4H, m, 2H ofPhOpipH-2, H-6, NHCH ₂), 3.65 (1H, m, 1H of PhOpipH-2, H-6), 3.40 (1H,m, 1H of PhOpipH-2, H-6), 1.94 (4H, m, PhOpipH-3, H-5); ¹⁹F nmr (CDCl₃)δ −123.4; m/z: 489 [M+H]⁺.

Compound 307:N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(3-(4-fluorobenzyloxy)azetidine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 8.76 (1H, m, pyH-6), 8.23 (1H, d, J 8.0 Hz, pyH-3),8.06 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.93 (1H, d, J 8.5 Hz, NH), 7.60(2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.46 (2H, d, J 8.0 Hz, 2H of C₆H₄CN),7.30 (2H, dd, J 8.5, 5.0 Hz, 2H of C₆H₄F), 7.05 (2H, t, 8.5 Hz, 2H ofC₆H₄F), 4.46 (2H, m, OCH ₂C₆H₄F), 4.44 (1H, m, 1H of AzH-2, H-4), 4.38(1H, d AB system, J 6.0 Hz, 1H of AzH-2, H-4), 4.21 (1H, m, 1H of AzH-2,H-4), 4.13 (1H, m 1H of AzH-2, H-6), 4.01 (1H, m pipH-4), 3.56 (2H, s,NCH ₂C₆H₄CN), 3.48 (1H, d, J 5.5 Hz, AzH-3), 2.81 (2H, m, 2H of pipH-2,H-6), 2.23 (2H, t, J 11.5 Hz, 2H of pipH-2, H-6), 2.02 (2H, m, 2H ofpipH-3, H-5), 1.65 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −113.6;m/z: 528 [M+H]⁺.

Compound 308:N-(1-(3,5-difluorobenzyl)piperidin-4-yl)-5-(3-(4-fluorobenzyloxy)azetidine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 8.70 (1H, dd, J 2.0, 1.0 Hz, pyH-6), 8.16 (1H, dd, J8.0, 1.0 Hz, pyH-3, 7.99 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.87 (1H, d, J8.0 Hz, NH), 7.24 (2H, dd, J 8.5, 5.0 Hz, 2H of C₆H₄F), 6.98 (2H, t, J8.5 Hz, 2H of C₆H₄F), 6.81 (2H, m, C₆H₃F₂H-2, H-6), 6.62 (1H, tt, J 9.0,2.5 Hz, C₆H₃F₂H-4), 4.40 (2H, m, 2H of AzH-2, H-4 or CH ₂C₆H₄F), 4.37(1H, m, 1H of AzH-2, H-4 or 1H of CH ₂C₆H₄F), 4.31 (1H, d AB system, J6.0 Hz, 1H of AzH-2, H-4 or 1H of CH ₂C₆H₄F), 4.15 (1H, m, 1H of AzH-2,H-4), 4.05 (1H, m, 1H of AzH-2, H-4), 3.94 (1H, m, pipH-4), 3.44 (2H, s,CH ₂C₆H₃F₂), 2.98 (1H, m, AzH-3), 2.78 (2H, m, 2H of pipH-2, H-6), 2.16(2H, t, J 11.5 Hz, 2H of pipH-2, H-6), 1.95 (2H, m, pipH-3, H-5), 1.59(2H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −110.5, −113.6; m/z: 539[M+H]⁺.

Compound 309:N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide.Compound 309 was synthesized as follows:

Coupling of the Benzoylpiperidine

To a mixture of 4-(4-methoxybenzoyl)piperidine hydrochloride (2.00 g,7.82 mmol, 1.0 eq) and 5-(methoxycarbonyl)pyridine-2-carboxylic acid(1.42 g, 7.82 mmol, 1.0 eq) in dimethylformamide (55 mL) was addedtriethylamine (2.72 mL, 19.55 mmol, 2.5 eq) followed by HATU (2.97 g,7.82 mmol, 1.0 eq). The reaction was stirred at room temperature for 4hours before partitioning between EtOAc (250 mL) and water-NaHCO₃ (1:1,200 mL). The organics were further washed with brine (150 mL), water(150 mL) and brine (150 mL), dried (Na₂SO₄) and concentrated underreduced pressure. Column chromatography (silica, 4-5% MeOH—CH₂Cl₂)yielded the coupled product (2.39 g, 80%) as a white foam; ¹H nmr(CDCl₃) δ 9.08 (1H, m, pyH-6), 8.29 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.84(2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 7.60 (1H, d, J 8.0 Hz, pyH-3), 6.84(2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 4.60 (1H, m, 1H of BzpipH-2, H-6),3.87 (3H, s, 1×OCH₃), 3.82 (1H, m, 1H of BzpipH-2, H-6), 3.77 (3H, s,1×OCH₃), 3.46 (1H, m, BzpipH-4), 3.19 (1H, ddd, J 14.0, 10.0, 4.0 Hz, 1Hof BzpipH-2, H-6), 3.02 (1H, m, 1H of BzpipH-2, H-6), 1.95-1.90 (1H, m,1H of BzpipH-3, H-5), 1.83-1.79 (3H, m, 3H of BzpipH-3, H-5); ¹³C nmr(CDCl₃) δ 199.9, 166.6, 165.0, 163.5, 157.7, 149.6, 138.1, 130.5, 128.5,126.3, 123.1, 113.9, 55.4, 52.5, 46.6, 42.6, 41.8, 28.8, 28.4; m/z: 383[M+H]⁺(found [M+H]⁺, 383.1515, C₂₁H₂₂N₂O₅ requires [M+H]⁺ 383.1602).

Hydrolysis of the Methyl Ester

To a solution of the pyridine methyl ester (2.39 g, 6.26 mmol, 1.0 eq)in tetrahydrofuran-methanol (2:1, 50 mL) was added an aqueous solutionof lithium hydroxide monohydrate (0.79 g, 18.77 mmol, 3.0 eq in 10 mL ofwater). The reaction was stirred at room temperature for 20 minutesbefore neutralizing with HCl (approximately 2.4 mL of a 6M solution).The reaction was concentrated to dryness to yield the crude carboxylicacid (3.08 g) as a white solid, which was used without purification; ¹Hnmr (D₆-DMSO) δ 8.97 (1H, m, pyH-6), 8.25 (1H, dd, J 8.0, 2.0 Hz,pyH-4), 7.98 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 7.51 (1H, dd, J 8.0, 1.0Hz, pyH-3), 7.04 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 4.50 (1H, m, 1H ofBzpipH-2, H-6), 3.83 (3H, s, 1×OCH₃), 3.76-3.62 (2H, m, 1H of BzpipH-2,H-6, BzpipH-4), 3.20 (1H, m, 1H of BzpipH-2, H-6), 3.00 (1H, m, 1H ofBzpipH-2, H-6), 1.86 (1H, m, 1H of BzpipH-3, H-5), 1.68 (1H, m, 1H ofBzpipH-3, H-5), 1.54 (2H, m, 2H of BzpipH-3, H-5); m/z: 369 [M+H]⁺.

Coupling of the Benzylaminopiperidine

To a suspension of the crude pyridine carboxylic acid (3.08 g, 6.26mmol, 1.0 eq) and 1-(4-cyanobenzyl)-4-aminopiperidine dihydrochloride(1.80 g, 6.26 mmol, 1.0 eq) in dimethylformamide (50 mL) was addedtriethylamine (3.05 mL, 21.91 mmol, 3.5 eq). HATU (2.38 g, 6.26 mmol,1.0 eq) was added forming a yellow solution, which was stirred at roomtemperature for 6 hours. The reaction was partitioned between EtOAc (200mL) and water-NaHCO₃ (1:1, 200 mL). The organics were washed with brine(150 mL), water (150 mL) and brine (150 mL) before drying (Na₂SO₄) andconcentrating under reduced pressure. MPLC (2→5% MeOH—CH₂Cl₂) yieldedCompound 309 (2.93 g, 83% over two steps) as a white solid; ¹H nmr(CDCl₃) δ 8.84 (1H, d, J 2.0 Hz, pyH-6), 8.06 (1H, dd, J 8.0, 2.0 Hz,pyH-4), 7.88 (2H, d, J 8.5 Hz, 2H of C₆H₄OCH₃), 7.56 (1H, d, J 7.5 Hz,pyH-3), 7.54 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.38 (2H, d, J 8.0 Hz, 2Hof C₆H₄CN), 6.89 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 6.24 (1H, d, J 7.5Hz, NH), 4.63 (1H, m, 1H of BzpipH-2, H-6), 3.98 (1H, m, pipH-4), 3.87(1H, m, 1H of BzpipH-2, H-6), 3.81 (3H, s, OCH₃), 3.50 (2H, s, CH₂C₆H₄CN), 3.47 (1H, m, BzpipH-4), 3.19 (1H, m, 1H of BzpipH-2, H-6),3.04 (1H, ddd, J 11.5, 10.0, 3.0 Hz, 1H of BzpipH-2, H-6), 2.77 (2H, m,2H of pipH-2, H-6), 2.14 (2H, dd, J 11.5, 10.0 Hz, 2H of pipH-2, H-6),1.97 (3H, m, 2H of pipH-3, H-5, 1H of BzpipH-3, H-5), 1.85-1.72 (3H, m,3H of BzpipH-3, H-5), 1.56 (2H, m, 2H of pipH-2, H-6); ¹³C nmr (CDCl₃) δ200.0, 167.0, 164.6, 163.7, 155.9, 147.4, 144.6, 135.9, 132.1, 130.9,130.6, 129.3, 128.5, 122.8, 119.0, 114.0, 110.8, 62.4, 55.5, 52.5, 47.4,46.7, 42.6, 42.0, 32.0, 28.8, 28.5; m/z: 566 [M+H]⁺ (found [M+H]⁺,566.2749, C₃₃H₃₅N₅O₄ requires [M+H]⁺ 566.2762).

Compound 310:(N-(1-(3,5-difluorobenzyl)piperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide.¹H nmr (CDCl₃) δ 8.90 (1H, d, J 2.0 Hz, pyH-6), 8.11 (1H, dd, J 8.5, 2.0Hz, pyH-4), 7.94 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 7.58 (1H, d, J 8.0Hz, pyH-3), 6.95 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 6.87 (2H, d, J 6.0Hz, C₆H₃F₂H-2, H-6), 6.67 (1H, tt, J 9.0, 2.0 Hz, C₆H₃F₂H-4), 6.52 (1H,d, J 7.5 Hz, NH), 4.70 (1H, m, 1H of BzpipH-2, H-6), 4.00 (1H, m,pipH-4), 3.92 (1H, m, 1H, BzpipH-2, H-6), 3.87 (3H, s, OCH₃), 3.53 (1H,m, BzpipH-4), 3.48 (2H, s, CH ₂C₆H₃F₂), 3.25 (1H, m, 1H of BzpipH-2,H-6), 3.11 (1H, m, 1H of BzpipH-2, H-6), 2.85 (2H, m, 2H of pipH-2,H-6), 2.19 (2H, dd, J 11.5, 10.0 Hz, 2H of pipH-2, H-6), 2.02 (3H, m, 2Hof pipH-3, H-5, 1H of BzpipH-3, H-5), 1.92-1.76 (3H, m, 3H of BzpipH-3,H-5), 1.63 (3H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −110.5; m/z:578 [M+H]⁺.

Compound 311:N-((cis)-4-(4-fluorophenoxy)cyclohexyl)-5-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 8.61 (1H, d, J 1.5 Hz, pyH-6), 8.25 (1H, d, J 8.0 Hz,pyH-3), 8.01 (1H, d, J 8.5 Hz, NH), 7.94 (2H, d, J 9.0 Hz, 2H ofC₆H₄OCH₃), 7.89 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.00-6.94 (4H, m, 2H ofC₆H₄OCH₃, 2H of C₆H₄F), 6.87 (2H, dd, J 9.0, 4.5 Hz, 2H of C₆H₄F), 4.66(1H, m, 1H of BzpipH-2, H-6), 4.42 (1H, m, cHexH-1), 4.09 (1H, m,cHexH-4), 3.88 (3H, s, OCH₃), 3.78 (1H, m, 1H of BzpipH-2, H-6), 3.54(1H, m, BzpipH-4), 3.16 (2H, m, 2H of BzpipH-2, H-6), 2.07-2.02 (3H, m,3H of cHexH-2, H-4, H-5, H-6, BzpipH-3, H-5), 1.90-1.75 (9H, m, 9H ofcHexH-2, H-3, H-5, H-6, BzpipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −123.6; m/z:560 [M+H]⁺.

Compound 312:N-((cis)-4-(4-fluorophenoxy)cyclohexyl)-5-(4-(4-fluorophenoxy)piperidine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 8.61 (1H, m, pyH-6), 8.25 (1H, d, J 8.0 Hz, pyH-3),8.01 (1H, d, J 8.5 Hz, NH), 7.89 (1H, dd, J 8.0, 2.0 Hz, pyH-4),7.01-6.94 (4H, m, 2×2H of C₆H₄F), 6.89-6.84 (4H, m, 2×2H of C₆H₄F), 4.52(1H, m, cHexH-1 or PhOpipH-4), 4.42 (1H, m, cHexH-1 or PhOpipH-4), 4.09(1H, m, cHexH-4)), 3.89 (2H, m, 2H of PhOpipH-2, H-6), 3.65 (1H, m, 1Hof PhOpipH-2, H-6), 3.36 (1H, m, 1H of PhOpipH-2, H-6), 2.06-1.75 (12H,m, PhOpipH-3, H-5, cHexH-2, H-3, H-5, H-6); ¹⁹F nmr (CDCl₃) δ −122.5,−123.5; m/z: 536 [M+H]⁺(found [M+H]⁺, 536.2416, C₃₀H₃₁F₂N₃O₄ requires[M+H]⁺ 536.2356).

Compound 313:5-(3-(4-cyanophenoxy)azetidine-1-carbonyl)-N-(1-(3,5-difluorobenzyl)piperidin-4-yl)picolinamide.¹H nmr (CDCl₃) δ 8.74 (1H, m, pyH-6), 8.19 (1H, d, J 8.0 Hz, pyH-3),8.03 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.86 (1H, m, NH), 7.55 (2H, d, J8.0 Hz, 2H of C₆H₄CN), 6.82 (2H, d, J 6.0 Hz, C₆H₃F₂H-2, H-6), 6.75 (2H,d, J 9.0 Hz, 2H of C₆H₄CN), 6.62 (1H, tt, J 9.0, 2.0 Hz, C₆H₃F₂H-4),5.02 (1H, m, AzH-3), 4.61 (2H, dd, J 10.5, 6.0 Hz, 2H of AzH-2, H-4),4.27 (2H, m, 2H of AzH-2, H-4), 3.94 (1H, m, pipH-4), 3.42 (2H, s,CH₂C₆H₃F₂), 2.76 (2H, m, 2H of pipH-2, H-6), 2.15 (2H, t, J 11.0 Hz, 2Hof pipH-2, H-6), 1.95 (2H, m, 2H of pipH-3, H-5), 1.58 (2H, m, 2H ofpipH-3, H-5); ¹⁹F nmr (CDCl₃) δ; m/z: 533 [M+H]⁺ (found [M+H]⁺,532.2160, C₂₉H₂₇F₂N₅O₃ requires [M+H]⁺ 532.2155).

Compound 314:5-(3-(4-cyanophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl)-N-(1-(3,5-difluorobenzyl)piperidin-4-yl)picolinamide.¹H nmr (CDCl₃) δ 8.71 (1H, d, J 2.5 Hz, pyH-6), 8.30 (1H, d, J 8.0 Hz,pyH-3), 8.00 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.93 (1H, d, J 8.5 Hz, NH),7.92 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.86 (2H, d, J 9.0 Hz, 2H ofC₆H₄CN), 6.88 (2H, d, J 6.0 Hz, C₆H₃F₂H-2, H-6), 6.68 (1H, tt, J 9.0,2.0 Hz, C₆H₃F₂H-4), 5.07 (2H, br s, 2H of triazolopyrazine), 4.27 (2H,br s, 2H of triazolopyrazine), 4.14 (2H, m, 2H of triazolopyrazine),4.02 (1H, m, pipH-4), 3.49 (2H, s, CH ₂C₆H₃F₂), 2.84 (2H, m, 2H ofpipH-2, H-6), 2.23 (2H, dd, J 11.5, 9.5 Hz, 2H of pipH-2, H-6), 2.03(2H, m, 2H of pipH-3, H-5), 1.68 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr(CDCl₃) δ−110.5; m/z: 583 [M+H]⁺.

Compound 315:N-((1s,4s)-4-(4-cyanophenoxy)cyclohexyl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide.¹H nmr (CDCl₃) δ 8.92 (1H, d, J 1.5 Hz, pyH-6), 8.14 (1H, dd, J 8.0, 2.0Hz, pyH-4), 7.94 (2H, d, J 9.5 Hz, 2H of C₆H₄OCH₃), 7.61 (1H, d, J 8.0Hz, pyH-3), 7.57 (2H, d, J 2H of C₆H₄CN), 6.96 (2H, d, J 9.0 Hz, 2H ofC₆H₄OCH₃), 6.95 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 6.43 (1H, d, J 8.0 Hz,NH), 4.70 (1H, m, 1H of BzpipH-2, H-6), 4.62 (1H, m, cHexH-1), 4.12 (1H,m, cHexH-4), 3.93 (1H, m, 1H of BzpipH-2, H-6), 3.88 (3H, s, OCH₃), 3.53(1H, m, BzpipH-4), 3.25 (1H, m, 1H of BzpipH-2, H-6), 3.10 (1H, m, 1H ofBzpipH-2, H-6), 2.11 (2H, m, 2H of cHexH-2, H-6), 2.04-1.73 (10H, m, 2Hof cHexH-2, H-6, cHexH-3, H-5, BzpipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −61.6,−114.9; m/z: 568 [M+H]⁺ (found [M+H]⁺, 567.2632, C₃₃H₃₄N₄O₅ requires[M+H]⁺ 567.2602).

Compound 316:N-((cis)-4-(4-fluorophenoxy)cyclohexyl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide.¹H nmr (CDCl₃) δ 8.93 (1H, d, J 1.5 Hz, pyH-6), 8.15 (1H, dd, J 8.0, 2.0Hz, pyH-4), 7.94 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 7.65 (1H, dd, J 8.0,0.5 Hz, pyH-3), 7.00-6.94 (4H, m, 2H of C₆H₄OCH₃, 2H of C₆H₄F), 6.86(2H, dd, J 9.0, 4.5 Hz, 2H of C₆H₄F), 6.29 (1H, d, J 8.0 Hz, NH), 4.70(1H, m, 1H of BzpipH-2, H-6), 4.44 (1H, m, cHexH-1), 4.11 (1H, m,cHexH-4), 3.95 (1H, m, 1H of BzpipH-2, H-6), 3.88 (3H, s, OCH₃), 3.52(1H, m, BzpipH-4), 3.26 (1H, ddd, J 10.5, 10.0, 3.5 Hz, 1H of BzpipH-2,H-6), 3.10 (ddd, J 11.5, 10.0, 3.0 Hz, 1H of BzpipH-2, H-6), 2.09-1.73(12H, m, BzpipH-3, H-5, cHexH-2, H-3, H-5, H-6); ¹⁹F nmr (CDCl₃) δ−123.4; m/z: 560 [M+H]⁺ (found [M+H]⁺, 560.2511, C₃₂H₃₄FN₃O₅ requires[M+H]⁺ 560.2555).

Compound 317:N-(1-(4-fluorobenzyl)piperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide.¹H nmr (CDCl₃) δ 8.90 (1H, d, J 2.0 Hz, pyH-6), 8.12 (1H, dd, J 8.5, 2.0Hz, pyH-4), 7.94 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 7.62 (1H, d, J 8.0Hz, pyH-3), 7.30-7.25 (2H, m, 2H of C₆H₄F), 7.02-6.94 (4H, m, 2H ofC₆H₄OCH₃, 2H of C₆H₄F), 6.32 (1H, d, J 8.5 Hz, NH), 4.69 (1H, m, 1H ofBzpipH-2, H-6), 4.03 (1H, m, pipH-4), 3.93 (1H, m, 1H of BzpipH-2, H-6),3.88 (3H, s, OCH₃), 3.52 (1H, m, BzpipH-4), 3.47 (2H, s, CH ₂C₆H₄F),3.25 (1H, d, J 11.0, 10.0, 4.0 Hz, 1H of BzpipH-2, H-6), 3.10 (1H, m, 1Hof BzpipH-2, H-6), 2.85 (2H, m, 2H of pipH-2, H-6), 2.16 (2H, t, J 11.5Hz, 2H of pipH-2, H-6), 2.02 (3H, m, 2H of pipH-3, H-5, 1H of BzpipH-3,H-5), 1.93-1.81 (3H, m, 3H of BzpipH-3, H-5), 1.68-1.54 (2H, m, 2H ofpipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −115.9; m/z: 560 [M+H]⁺ (found [M+H]⁺,559.2708, C₃₂H₃₅FN₄O₄ requires [M+H]⁺ 538.2715).

Compound 318:6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)-N-(1-(4-methoxybenzyl)piperidin-4-yl)nicotinamide.¹H nmr (CDCl₃) δ 8.90 (1H, d, J 2.0 Hz, pyH-6), 8.12 (1H, dd, J 8.5, 2.0Hz, pyH-4), 7.94 (2H, d, J 9.0 Hz, 2H of COC₆ H ₄OCH₃), 7.62 (1H, d, J8.0 Hz, pyH-3), 7.22 (2H, d, J 8.5 Hz, 2H of CH₂C₆ H ₄OCH₃), 6.95 (2H,d, J 9.0 Hz, 2H of COC₆ H ₄OCH₃), 6.85 (2H, d, J 8.5 Hz, 2H of CH₂C₆ H₄OCH₃), 6.30 (1H, d, J 8.0 Hz, NH), 4.69 (1H, m, 1H of BzpipH-2, H-6),4.00 (1H, m, pipH-4), 3.93 (1H, m, 1H of BzpipH-2, H-6), 3.87 (3H, s,1×OCH₃), 3.80 (3H, s, 1×OCH₃), 3.52 (1H, m, BzpipH-4), 3.45 (2H, s, CH₂C₆H₄OCH₃), 3.25 (1H, m, 1H of BzpipH-2, H-6), 3.10 (1H, ddd, J 12.0,10.0, 3.0 Hz, 1H of BzpipH-2, H-6), 2.85 (2H, m, 2H of pipH-2, H-6),2.14 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 2.02 (3H, m, 2H of pipH-3,H-5, 1H of BzpipH-3, H-5), 1.92-1.81 (3H, m, 3H of BzpipH-3, H-5), 1.59(2H, m, 2H of pipH-3, H-5); m/z: 571 [M+H]⁺(found [M+H]⁺, 571.2895,C₃₃H₃₈N₄O₅ requires [M+H]⁺ 571.2915).

Compound 319:6-(4-(4-cyanophenoxy)piperidine-1-carbonyl)-N-(1-(4-methoxybenzyl)piperidin-4-yl)nicotinamide.¹H nmr (CDCl₃) δ 8.90 (1H, d, J 1.5 Hz, pyH-6), 8.12 (1H, dd, J 8.0, 2.0Hz, pyH-4), 7.62 (1H, d, J 8.0 Hz, pyH-3), 7.59 (2H, d, J 9.0 Hz, 2H ofC₆H₄OCH₃ or C₆H₄CN), 7.23 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃ or C₆H₄CN),6.96 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃ or C₆H₄CN), 6.85 (2H, d, J 8.5 Hz,2H of C₆H₄OCH₃ or C₆H₄CN), 6.43 (1H, d, J 7.5 Hz, NH), 4.69 (1H, m,PhOpipH-4), 4.01 (1H, m, pipH-4), 3.90 (2H, m, 2H of PhOpipH-2, H-6),3.79 (3H, s, OCH₃), 3.70 (1H, m, 1H of PhOpipH-2, H-6), 3.51 (1H, m, 1Hof PhOpipH-2, H-6), 3.48 (2H, s, CH ₂C₆H₄OCH₃), 2.88 (2H, m, 2H ofpipH-2, H-6), 2.16 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 2.03-1.93 (5H,m, 2H of pipH-3, H-5, 3H of PhOpipH-3, H-5), 1.86 (1H, m, 1H ofPhOpipH-3, H-5), 1.62 (2H, m, 2H of pipH-3, H-5); m/z: 554 [M+H]⁺.

Compound 320:6-(4-(4-cyanophenoxy)piperidine-1-carbonyl)-N-(1-(4-fluorobenzyl)piperidin-4-yl)nicotinamide.¹H nmr (CDCl₃) δ 8.86 (1H, d, J 1.5 Hz, pyH-6), 8.10 (1H, dd, J 8.5, 2.0Hz, pyH-4), 7.64 (1H, d, J 8.5 Hz, pyH-3), 7.53 (2H, d, J 9.0 Hz, 2H ofC₆H₄CN), 7.25 (2H, m, 2H of C₆H₄F), 6.96 (1H, t, J 8.5 Hz, 2H of C₆H₄F),6.90 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 6.16 (1H, m, NH), 4.63 (1H, m,PhOpipH-4), 3.99 (1H, m, pipH-4), 3.84 (2H, m, 2H of PhOpipH-2, H-6),3.65 (1H, m, 1H of PhOpipH-2, H-6), 3.51 (2H, s, CH ₂C₆H₄F), 3.48 (1H,m, 1H of PhOpipH-2, H-6), 2.88 (2H, m, 2H of pipH-2, H-6), 2.19 (2H, m,2H of pipH-2, H-6), 2.02-1.92 (6H, m, 2H of pipH-3, H-5, PhOpipH-3,H-5), 1.60 (2H, m, 2H of pipH-3, H-5); m/z: 543 [M+H]⁺.

Compound 321:N-((cis)-4-(4-cyanophenoxy)cyclohexyl)-6-(4-(4-cyanophenoxy)piperidine-1-carbonyl)nicotinamide.¹H nmr (CDCl₃) δ 8.93 (1H, d, J 2.0 Hz, pyH-6), 8.15 (1H, dd, J 8.5, 2.0Hz, pyH-4), 7.62 (1H, d, J 8.5 Hz, pyH-3), 7.58 (2H, d, J 8.5 Hz, 2H of1×C₆H₄CN), 7.56 (2H, d, J 9.0 Hz, 2H of 1×C₆H₄CN), 6.95 (2H, d, J 8.5Hz, 2H of 1×C₆H₄CN), 6.93 (2H, d, J 9.0 Hz, 2H of 1×C₆H₄CN), 6.57 (1H,d, J 8.0 Hz, NH), 4.69 (1H, pentet, J 3.0 Hz, PhOpipH-4), 4.61 (1H, m,cHexH-1), 4.10 (1H, m, cHexH-4), 3.90 (2H, m, 2H of PhOpipH-2, H-6),3.70 (1H, m, 1H of PhOpipH-2, H-6), 3.49 (1H, m, 1H of PhOpipH-2, H-6),2.11-2.04 (3H, m, 3H of PhOpipH-3, H-5, cHexH-2, H-3, H-5, H-6),1.98-1.73 (9H, m, 9H of PhOpipH-3, H-5, cHexH-2, H-3, H-5, H-6); m/z:550 [M+H]⁺.

Compound 322:6-(4-(4-cyanophenoxy)piperidine-1-carbonyl)-N-(1-(3,5-difluorobenzyl)piperidin-4-yl)nicotinamide.¹H nmr (CDCl₃) δ 8.84 (1H, d, J 2.0 Hz, pyH-6), 8.07 (1H, dd, J 8.0, 2.0Hz, pyH-4), 7.59 (1H, d, J 8.0 Hz, pyH-3), 7.53 (2H, d, J 9.0 Hz, 2H ofC₆H₄CN), 6.90 (2H, d, J 9.5 Hz, 2H of C₆H₄CN), 6.80 (2H, m, C₆H₃F₂H-2,H-6), 6.62 (1H, tt, J 9.0, 2.0 Hz, C₆H₃F₂H-4), 6.21 (1H, d, J 8.0 Hz,NH), 4.64 (1H, heptet, J 3.0 Hz, PhOpipH-4), 3.96 (1H, m, pipH-4), 3.85(2H, m, 2H of PhOpipH-2, H-6), 3.66 (1H, ddd, J 13.0, 9.0, 3.5 Hz, 1H ofPhOpipH-2, H-6), 3.47 (1H, m, 1H of PhOpipH-2, H-6), 3.42 (2H, s, CH₂C₆H₃F₂), 2.78 (2H, m, 2H of pipH-2, H-6), 2.13 (2H, t, J 11.5 Hz, 2H ofpipH-2, H-6), 2.00-1.95 (5H, m, 2H of pipH-3, H-5, 3H of PhOpipH-3,H-5), 1.81 (1H, m, 1H of PhOpipH-3, H-5), 1.56 (2H, m, 2H of pipH-3,H-5); ¹⁹F nmr (CDCl₃) δ −110.5; m/z: 560 [M+H]⁺.

Compound 323:N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(4-cyanophenoxy)piperidine-1-carbonyl)nicotinamide.¹H nmr (CDCl₃) δ 8.90 (1H, m, pyH-6), 8.13 (1H, dd, J 8.0, 2.0 Hz,pyH-4), 7.63 (1H, d, J 8.0 Hz, pyH-3), 7.61 (2H, d, J 8.5 Hz, 2H of1×C₆H₄CN), 7.58 (2H, d, J 8.5 Hz, 2H of 1×C₆H₄CN), 7.45 (2H, d, J 8.5Hz, 1×C₆H₄CN), 6.96 (2H, d, J 9.0 Hz, 2H of 1×C₆H₄CN), 6.94 (1H, d, J8.0 Hz, NH), 4.70 (1H, pentet, J 3.0 Hz, PhOpipH-4), 4.01 (1H, m,pipH-4), 3.90 (2H, m, 2H of PhOpipH-2, H-6), 3.70 (1H, m, 1H ofPhOpipH-2, H-6), 3.56 (2H, s, CH ₂C₆H₄CN), 2.83 (2H, m, 2H of pipH-2,H-6), 2.20 (2H, t, J 11.5 Hz, 2H of pipH-2, H-6), 2.02 (5H, m, 2H ofpipH-3, H-5, 3H of PhOpipH-3, H-5), 1.87 (1H, m, 1H of PhOpipH-3, H-5),1.61 (2H, m, 2H of pipH-3, H-5); m/z: 549 [M+H]⁺.

Compound 324:6-(4-(4-cyanophenoxy)piperidine-1-carbonyl)-N-((cis)-4-(4-fluorophenoxy)cyclohexyl)nicotinamide.¹H nmr (CDCl₃) δ 8.94 (1H, d, J 1.5 Hz, pyH-6), 8.16 (1H, dd, J 8.0, 2.0Hz, pyH-4), 7.67 (1H, d, J 8.5 Hz, pyH-3), 7.59 (2H, d, J 9.0 Hz, 2H ofC₆H₄CN), 6.97 (4H, m, 2H of C₆H₄CN, 2H of C₆H₄F), 6.85 (2H, m, 2H ofC₆H₄F), 6.28 (1H, d, J 8.5 Hz, NH), 4.70 (1H, m, PhOpipH-4), 4.44 (1H,br s, cHexH-1), 4.11 (1H, m, cHexH-4), 3.90 (2H, m, 2H of PhOpipH-2,H-6), 3.72 (1H, m, 1H of PhOpipH-2, H-6), 3.54 (1H, m, 1H of PhOpipH-2,H-6), 2.09-1.98 (5H, m, 5H of cHexH-2, H-3, H-5, H-6, PhOpipH-3, -5),1.90-1.73 (7H, m, 7H of cHexH-2, H-3, H-5, H-6, PhOpipH-3, H-5); ¹⁹F nmr(CDCl₃) δ −123.3; m/z: 543 [M+H]⁺(found [M+H]⁺, 543.2511, C₃₁H₃₁FN₄O₄requires [M+H]⁺ 543.2402).

Compound 325:N-(6-(4-fluorophenoxy)pyridin-3-yl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide.¹H nmr (CDCl₃) δ 9.57 (1H, s, NH), 8.94 (1H, m, pyH-6), 8.47 (1H, d, J2.5 Hz, N,O-pyH-6), 8.32 (1H, dd, J 9.0, 2.5 Hz, N,O-pyH-4), 8.12 (1H,dd, J 8.0, 2.0 Hz, pyH-4), 7.94 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 7.42(1H, d, J 8.0 Hz, pyH-3), 7.11-7.06 (4H, m, 2H of C₆H₄OCH₃, 2H ofC₆H₄F), 6.97-6.93 (3H, m, 2H of C₆H₄F, N,O-pyH-3), 4.68 (1H, m, 1H ofBzpipH-2, H-6), 3.88 (3H, s, OCH₃), 3.81 (1H, m, 1H of BzpipH-2, H-6),3.54 (1H, m, BzpipH-4), 3.28-3.11 (2H, m, 2H of BzpipH-2, H-6), 2.02(1H, m, 1H of BzpipH-3, H-5), 1.92-1.82 (3H, m, 3H of BzpipH-3, H-5);¹⁹F nmr (CDCl₃) δ −118.6; m/z: 555 [M+H]⁺ (found [M+H]⁺, 555.2267,C₃₁H₂₇FN₄O₅ requires [M+H]⁺ 555.2039).

Compound 326:6-(4-(4-cyanophenoxy)piperidine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3-yl)nicotinamide.¹H nmr (CDCl₃) δ 9.42 (1H, s, NH), 8.94 (1H, m, pyH-6), 8.42 (1H, d, J2.5 Hz, N,O-pyH-6), 8.33 (1H, dd, J 9.0, 2.5 Hz, N,O-pyH-4), 8.12 (1H,dd, J 8.0, 2.0 Hz, pyH-4), 7.60 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 7.44(1H, d, J 8.0 Hz, pyH-3), 7.08 (4H, m, 2H of C₆H₄CN, 2H of C₆H₄F),6.97-6.94 (3H, m, 2H of C₆H₄F, N, O-pyH-3), 4.71 (1H, m, PhOpipH-4),3.99 (1H, m, 1H of PhOpipH-2, 6), 3.86 (1H, m, 1H of PhOpipH-2, H-6),3.65 (1H, m, 1H of PhOpipH-2, H-6), 3.44 (1H, m, 1H of PhOpipH-2, H-6),2.07-1.94 (3H, m, 3H of PhOpipH-3, H-5), 1.88 (1H, m, 1H of PhOpipH-3,H-5); ¹⁹F nmr (CDCl₃) δ −118.3; m/z: 538 [M+H] (found [M+H] 538.1985,C₃₀H₂₄FN₅O₄ requires [M+H] 538.1885).

Compound 327:6-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(1-(4-methoxybenzyl)piperidin-4-yl)nicotinamide.¹H nmr (CDCl₃) δ 8.89 (1H, d, J 1.5 Hz, pyH-6), 8.12 (1H, dd, J 8.5, 2.0Hz, pyH-4), 7.62 (1H, d, J 7.5 Hz, pyH-3), 7.30-7.21 (4H, m, 2H ofC₆H₄F, 2H of C₆H₄OCH₃), 7.00 (2H, t, J 8.5 Hz, 2H of C₆H₄F), 6.86 (2H,d, J 9.0 Hz, 2H of C₆H₄OCH₃), 6.34 (1H, d, J 8.0 Hz, NH), 4.02 (1H, m,pipH-4), 3.80 (5H, m, 2H of piz, OCH₃), 3.52 (2H, m, 2H of piz), 3.50(2H, s, CH ₂C₆H₄F or CH ₂C₆H₄OCH₃), 3.49 (2H, s, CH ₂C₆H₄F or CH₂C₆H₄OCH₃), 2.89 (2H, m, 2H of pipH-2, H-6), 2.54 (2H, t, J 5.0 Hz, 2Hof piz), 2.41 (2H, m, t, J 5.0 Hz, 2H of piz), 2.19 (2H, t, J 11.5 Hz,2H of pipH-2, H-6), 2.02 (2H, m, 2H of pipH-3, H-5), 1.63 (2H, m, 2H ofpipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −115.5; m/z: 546 [M+H]

Compound 328:6-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(1-(4-fluorobenzyl)piperidin-4-yl)nicotinamide.¹H nmr (CDCl₃) δ 8.92 (1H, m, pyH-6), 8.15 (1H, dd, J 8.0, 2.0 Hz,pyH-4), 7.62 (1H, d, J 8.0 Hz, pyH-3), 7.36-7.25 (4H, m, 2×2H of C₆H₄F),7.06-6.97 (4H, m, 2×2H of C₆H₄.F), 6.60 (1H, d, J 7.0 Hz, NH), 4.06 (1H,m, pipH-4), 3.80 (2H, t, J 5.0 Hz, 2H of piz), 3.63 (2H, s, 1×CH₂C₆H₄F),3.51 (4H, m, 2H of piz, 1×CH₂C₆H₄F), 2.99 (2H, m, 2H of pipH-2, H-6),2.54 (2H, t, J 5.0 Hz, 2H of piz), 2.41 (2H, t, J 5.0 Hz, 2H of piz),2.33 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 2.06 (2H, m, 2H of pipH-3,H-5), 1.75 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ−114.5, −115.4;m/z: 534 [M+H]

Compound 329:5-(4-(3,4-difluorobenzoyl)piperidine-1-carbonyl)-N-(1-(4-methoxybenzyl)piperidin-4-yl)picolinamide.¹H nmr (CDCl₃) δ 8.52 (1H, m, pyH-6), 8.16 (1H, d, J 8.0 Hz, pyH-3),7.84 (1H, d, J 7.0 Hz, NH), 7.79 (2H, m, pyH-4, 1H of C₆H₃F₂), 7.87 (2H,d, J 9.0 Hz, 2H of C₆H₄OCH₃), 6.93 (1H, m, 1H of C₆H₃F₂), 6.85 (1H, m,1H of C₆H₃F₂), 6.79 (2H, d, J 8.5 Hz, 2H of C₆H₄OCH₃), 4.57 (1H, m,BzpipH-4), 3.93 (1H, m, pipH-4), 3.73 (3H, s, OCH₃), 3.65 (1H, m, 1H ofBzpipH-2, H-6), 3.42 (2H, s, CH ₂C₆H₄OCH₃), 3.34 (1H, m, BzpipH-4), 3.06(2H, m, 2H of BzpipH-2, H-6), 2.79 (2H, m, 2H of pipH-2, H-6), 2.13 (2H,dd, J 11.0, 9.5 Hz, 2H of pipH-2, H-6), 1.97-1.80 (4H, m, 2H of pipH-3,H-5, 2H of BzpipH-3, H-5), 1.75-1.52 (4H, m, 2H of pipH-3, H-5, 2H ofBzpipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −101.2, −106.6; m/z: 577 [M+H]

Compound 330:5-(4-(3,4-difluorobenzoyl)piperidine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3-yl)picolinamide.¹H nmr (CDCl₃) δ 8.77 (1H, m, 1×ArH), 8.51 (1H, d, J 2.5 Hz, 1×ArH),8.45 (2H, dd, J 5.0, 3.5 Hz, 2×ArH), 8.42 (1H, s, 1×ArH), 8.05 (1H, dd,J 8.0, 2.0 Hz, 1×ArH), 7.99 (1H, m, 1×ArH), 7.22-7.18 (4H, m, 4×ArH),7.15-6.56 (3H, m, 3×ArH), 4.75 (1H, m, 1H of BzpipH-2, H-6), 3.84 (1H,m, 1H of BzpipH-2, H-6), 3.53 (1H, m, BzpipH-4), 3.33-3.22 (2H, m, 2H ofBzpipH-2, H-6), 2.07-2.02 (2H, m, 2H of BzpipH-3, H-5), 1.86 (2H, m, 2Hof BzpipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −101.1, −106.5, −118.6; m/z: 561[M+H]⁺.

Compound 331:5-(4-(2,4-difluorobenzoyl)piperidine-1-carbonyl)-N-(1-(4-methoxybenzyl)piperidin-4-yl)picolinamide.¹H nmr (CDCl₃) δ 8.59 (1H, d, J 1.5 Hz, pyH-6), 8.23 (1H, d, J 8.0 Hz,pyH-3), 7.92-7.84 (3H, m, NH, pyH-4, 1H of C₆H₃F₂), 7.24 (2H, d, J 9.0Hz, 2H of C₆H₄OCH₃), 7.00 (1H, m, 1H of C₆H₃F₂), 6.88 (1H, m, 1H ofC₆H₃F₂), 6.86 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 4.64 (1H, m, 1H ofBzpipH-2, H-6), 4.00 (1H, m pipH-4), 3.80 (3H, s, OCH₃), 3.74 (1H, m,BzpipH-2, H-6), 3.48 (2H, s, CH ₂C₆H₄OCH₃), 3.41 (1H, m, BzpipH-4), 3.13(2H, m, 2H of BzpipH-2, H-6), 2.86 (2H, m, 2H of pipH-2, H-6), 2.19 (2H,dd, J 11.0, 8.5 Hz, 2H of pipH-2, H-6), 1.99 (4H, m, 2H of pipH-3, H-5,2H of BzpipH-3, H-5), 1.76-1.63 (4H, m, 2H of pipH-3, H-5, 2H ofBzpipH-3, H-5); ¹⁹F nmr (CDCl₃) δ−101.3, −11.6.5; m/z: 577 [M+H]⁺.

Compound 332:N-((cis)-4-(4-cyanophenoxy)cyclohexyl)-6-(4-(4-fluorobenzyl)piperazine-1-carbonyl)nicotinamide.¹H nmr (CDCl₃) δ 8.91 (1H, d, J 1.5 Hz, pyH-6), 8.14 (1H, dd, J 8.0, 2.0Hz, pyH-4), 7.67 (1H, d, J 8.0 Hz, pyH-3), 7.58 (2H, d, J 9.0 Hz,C₆H₄CN), 7.28 (2H, m, 2H of C₆H₄F), 7.00 (2H, t, J 9.0 Hz, 2H of C₆H₄F),6.95 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 6.19 (1H, d, J 8.0 Hz, NH), 4.62(1H, m, cHexH-1), 4.12 (1H, m, cHexH-4), 3.82 (2H, m, 2H of piz), 3.51(4H, m, 2H of piz, CH ₂C₆H₄F), 2.55 (2H, m, 2H of piz), 2.42 (2H, m, 2Hof piz), 2.10 (2H, m, 2H of cHexH-2, H-6), 1.94 (2H, m, 2H of cHexH-2,H-6 or 2H of cHexH-3, H-5), 1.84-1.71 (4H, 2H of cHexH-3, H-5, 2H ofcHexH-2, H-6 or cHexH-3, H-5); ¹⁹F nmr (CDCl₃) δ −115.5; m/z: 542[M+H]⁺.

Compound 333: tert-butyl4-(6-(4-(4-cyanophenoxy)piperidine-1-carbonyl)nicotinamido)piperidine-1-carboxylate.¹H nmr (CDCl₃) δ 8.91 (1H, d, J 2.0 Hz, pyH-6), 8.11 (1H, dd, J 8.5, 2.0Hz, pyH-4), 7.58 (2H, d, J 9.5 Hz, 2H of C₆H₄CN), 7.51 (1H, d, J 8.5 Hz,pyH-3), 7.21 (1H, d, J 8.0 Hz, NH), 6.94 (2H, d, J 9.0 Hz, 2H ofC₆H₄CN), 4.68 (1H, m, PhOpipH-4), 4.09 (3H, m, 3H of PhOpipH-2, H-6,pipH-2, H-4, H-6), 3.94-3.80 (2H, m, 2H of PhOpipH-2, H-6, pipH-2, H-4,H-6), 3.07-3.62 (1H, m, 1H of PhOpipH-2, H-6, pipH-2, H-4, H-6), 3.44(1H, m, 1H of PhOpipH-2, H-6, pipH-2, H-4, H-6), 2.85 (2H, t, J 12.0 Hz,2H of pipH-2, H-6), 2.10-1.80 (8H, m, PhOpipH-3, H-5, pipH-3, H-5), 1.45(9H, s, C(CH₃)₃); m/z: 534 [M+H]⁺, 478 [M+H—C₄H₈]⁺.

Compound 334:6-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3-yl)nicotinamide.¹H nmr (CDCl₃) δ 9.56 (1H, s, NH), 8.83 (1H, d, J 2.0 Hz, N,O-pyH-6),8.38 (1H, d, J 2.5 Hz, pyH-6), 8.27 (1H, dd, J 8.5, 2.5 Hz, pyH-4), 8.00(1H, dd, J 8.5, 2.0 Hz, N,O-pyH-4), 7.31 (1H, d, J 8.0 Hz, N,O-pyH-3),7.20 (2H, m, 2H of 1×C₆H₄F), 7.03 (4H, m, 4H of 1×C₆H₄F), 6.94 (2H, t, J9.0 Hz, 2H of 1×C₆H₄F), 6.88 (1H, d, J 9.0 Hz, pyH-3), 3.76 (2H, m, 2Hof piz), 3.44 (2H, s, CH ₂C₆H₄F), 3.36 (2H, m, 2H of piz), 2.47 (2H, m,2H of piz), 2.33 (2H, m, 2H of piz); ¹⁹F nmr (CDCl₃) δ −115.3, −118.5;m/z: 530 [M+H]⁺.

Compound 335:6-(4-(4-cyanophenoxy)piperidine-1-carbonyl)-N-(piperidin-4-yl)nicotinamide.¹H nmr (CDCl₃) δ 8.90 (1H, d, J 2.0 Hz, pyH-6), 8.12 (1H, dd, J 8.0, 2.0Hz, pyH-4), 7.58 (3H, m, 2H of C₆H₄CN, NH), 6.95 (2H, d, J 9.0 Hz, 2H ofC₆H₄CN), 6.68 (1H, d, J 8.0 Hz, pyH-3), 4.69 (1H, m, PhOpipH-4), 4.07(1H, m, pipH-4), 3.89 (2H, m, 2H of PhOpipH-2, H-6), 3.69 (1H, m, 1H ofPhOpipH-2, H-6), 3.47 (1H, m, 1H of PhOpipH-2, H-6), 3.12 (2H, m, 2H ofpipH-2, H-6), 2.74 (2H, m, 2H of pipH-2, H-6), 2.10-1.81 (6H, m,PhOpipH-3, H-5, 2H of pipH-3, H-5), 1.48 (2H, m, 2H of pipH-3, H-5);m/z: 434 [M+H]⁺.

Compound 336:6-(4-(4-cyanophenoxy)piperidine-1-carbonyl)-N-(1-(4-(pyrrolidin-1-yl)benzyl)piperidin-4-yl)nicotinamide.¹H nmr (CDCl₃) δ 8.95 (1H, d, J 1.5 Hz, pyH-6), 8.19 (1H, dd, J 8.5, 2.0Hz, pyH-4), 7.67 (1H, d, J 8.0 Hz, pyH-3), 7.59 (2H, d, J 9.0 Hz, 2H ofC₆H₄CN), 7.20 (2H, d, J 9.0 Hz, 2H of C₆H₄N), 6.96 (2H, d, J 9.0 Hz, 2Hof C₆H₄CN), 6.72 (1H, d, J 7.0 Hz, NH), 6.53 (2H, d, J 9.0 Hz, 2H ofC₆H₄N), 4.69 (1H, m, PhOpipH-4), 4.08 (1H, m, pipJ-4), 3.93-3.86 (2H, m,2 h of PhOpipH-2, H-6), 3.71 (1H, m, 1H of PhOpipH-2, H-6), 3.65 (2H, s,CH₂C₆H₄N), 3.50 (1H, m, PhOpipH-2, H-6), 3.28 (4H, m, pyrrolidineH-2,H-5), 3.09 (2H, m, 2H of pipH-2, H-6), 2.35 (6H, m, 2H of pipH-2, H-6,pyrrolidineH-3, H-4), 2.08-1.86 (8H, m, pipH-3, H-5, PhOpipH-3, H-5);m/z: 594 [M+H]⁺.

Compound 337:6-(4-(4-cyanophenoxy)piperidine-1-carbonyl)-N-(1-(4-morpholinobenzyl)piperidin-4-yl)nicotinamide.¹H nmr (CDCl₃) δ 8.92 (1H, m, pyH-6), 8.15 (1H, dd, J 8.0, 2.0 Hz,pyH-4), 7.69 (1H, d, J 8.5 Hz, pyH-3), 7.59 (2H, d, J 9.0 Hz, 2H ofC₆H₄CN), 7.25 (2H, m, 2H of C₆H₄N), 6.96 (2H, d, J 9.5 Hz, 2H ofC₆H₄CN), 6.88 (2H, d, J 9.0 Hz, 2H of C₆H₄N), 6.29 (1H, d, J 7.0 Hz,NH), 4.70 (1H, m, PhOpipH-4), 4.04 (1H, m, pipH-4), 3.91 (2H, m, 2H ofPhOpipH-2, H-6), 3.87, 3.85 (4H, d AB system, J 5.0 Hz, 2×morpholineH-2,H-6), 3.72 (1H, m, 1H of PhOpipH-2, H-6), 3.55 (3H, m, CH₂C₆H₄N, 1H ofPhOpipH-2, H-6), 3.17, 3.15 (4H, d AB system, J 4.5 Hz, 2×morpholineH-3,H-5), 2.96 (2H, m, 2H of pipH-2, H-6), 2.24 (2H, dd, J 12.0, 10.5 Hz, 2Hof pipH-2, H-6), 2.02 (4H, m, 2H of pipH-3, H-5, 2H of PhOpipH-3, H-5),1.81-1.69 (4H, m, 2H of pipH-3, H-5, PhOpipH-3, H-5); m/z: 610 [M+H]⁺.

Compound 338:6-(4-(4-cyanophenoxy)piperidine-1-carbonyl)-N-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)nicotinamide.¹H nmr (CDCl₃) δ 8.92 (1H, d, J 2.0 Hz, pyH-6), 8.16 (1H, dd, J 8.5, 2.0Hz, pyH-4), 7.69 (1H, d, J 8.0 Hz, pyH-3), 7.59 (2H, d, J 9.0 Hz, 2H ofC₆H₄CN), 7.38 (2H, d, J 8.5 Hz, 2H of C₆H₄OCF₃), 7.18 (2H, d, J 8.5 Hz,2H of C₆H₄OCF₃), 6.96 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 6.22 (1H, m, NH),4.70 (1H, m, PhOpipH-4), 4.06 (1H, m, pipH-4), 3.94-3.88 (2H, m, 2H ofPhOpipH-2, H-6), 3.71 (1H, m, 1H of PhOpipH-2, H-6), 3.58 (2H, s,CH₂C₆H₄OCF₃), 3.50 (1H, m, PhOpipH-2, H-6), 2.93 (2H, m, 2H of pipH-2,H-6), 2.25 (2H, dd, J 11.5, 10.5 Hz, 2H of pipH-2, H-6), 2.05 (4H, m,pipH-3, H-5, 2H of PhOpipH-3, H-5), 1.84-1.67 (4H, m, 2H of pipH-3, H-5,2H of PhOpipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −57.9; m/z: 609 [M+H]⁺.

Compound 339:N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-(trifluoromethyl)phenyl)piperazine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 8.63 (1H, m, pyH-6), 8.27 (1H, d, J 8.0 Hz, pyH-3),7.93 (1H, m, NH), 7.92 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.61 (2H, d, J8.5 Hz, 2H of C₆H₄CN or C₆H₄CF₃), 7.51 (2H, d, J 8.5 Hz, 2H of C₆H₄CN orC₆H₄CF₃), 7.46 (2H, d, J 8.5 Hz, 2H of C₆H₄CN or C₆H₄CF₃), 6.94 (2H, d,J 8.5 Hz, 2H of C₆H₄CN or C₆H₄CF₃), 4.00 (3H, m, pipH-4, 2H of piz),3.57 (4H, m, CH₂C₆H₄CN, 2H of piz), 3.31 (4H, m, 4H of piz), 2.82 (2H,m, 2H of pipH-2, H-6), 2.24 (2H, dd, J 11.5, 9.5 Hz, 2H of pipH-2, H-6),2.02 (H, m, 2H of pipH-3, H-5), 1.65 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr(CDCl₃) δ −61.6; m/z: 577 [M+H]⁺.

Compound 340:N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-cyanophenyl)piperazine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 8.63 (1H, m, pyH-6), 8.25 (1H, d, J 8.0 Hz, pyH-3),7.90 (2H, m, NH, pyH-4), 7.60 (2H, d, J 8.5 Hz, 2H of 1×C₆H₄CN), 7.52(2H, d, J 9.0 Hz, 2H of 1×C₆H₄CN), 7.45 (2H, d, J 8.5 Hz, 2H of1×C₆H₄CN), 6.87 (2H, d, J 9.5 Hz, 2H of 1×C₆H₄CN), 4.03-3.90 (3H, m,pipH-4, 2H of piz), 3.60 (2H, m, 2H of piz), 3.56 (2H, s, CH ₂C₆H₄CN),3.36 (4H, m, 4H of piz), 2.80 (2H, m, 2H of pipH-2, H-6), 2.23 (2H, dd,J 11.0, 10.0 Hz, 2H of pipH-2, H-6), 2.01 (2H, m, 2H of pipH-3, H-5),1.65 (2H, m, 2H of pipH-3, H-5); m/z: 534 [M+H]⁺.

Compound 341:N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-fluorophenyl)piperazine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 8.63 (1H, m, pyH-6), 8.26 (1H, dd, J 8.0, 1.0 Hz,pyH-3), 7.93 (1H, d, J 8.0 Hz, NH), 7.91 (1H, dd, J 8.0, 2.0 Hz, pyH-4),7.62 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.46 (2H, d, J 8.0 Hz, 2H ofC₆H₄CN), 6.99 (2H, m, 2H of C₆H₄F), 6.89 (2H, m, 2H of C₆H₄F), 3.99 (3H,m, pipH-4, 2H of piz), 3.57 (3H, m, CH ₂C₆H₄CN, 2H of piz), 3.18 (2H, m,2H of piz), 3.07 (2H, m, 2H of piz), 2.82 (2H, m, 2H of pipH-2, H-6),2.24 (2H, mdd, J 11.0, 10.0 Hz, 2H of pipH-2, H-6), 2.03 (2H, m, 2H ofpipH-3, H-5), 1.65 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −122.6;m/z: 527 [M+H]⁺.

Compound 342:5-(4-(2,4-difluorobenzoyl)piperidine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3-yl)picolinamide.¹H nmr (CDCl₃) δ 9.90 (1H, s, NH), 8.67 (1H, m, 1×pyH-6), 8.41 (1H, d, J2.0 Hz, 1×pyH-6), 8.36-8.33 (2H, m, 2×pyH), 7.95 (1H, dd, J 8.0, 2.0 Hz,1×pyH-4), 7.89 (1H, m, 1H of C₆H₃F₂), 7.13-7.08 (4H, m, 4H of C₆H₄F),7.00 (1H, m, 1H of C₆H₃F₂), 6.97 (1H, d, J 9.0 Hz, 1×pyH-3), 6.90 (1H,ddd, J 11.5, 9.0, 2.5 Hz, 1H of C₆H₃F₂), 4.64 (1H, m, 1H of BzpipH-2,H-6), 3.75 (1H, m, 1H of BzpipH-2, H-6), 3.43 (1H, m, BzpipH-4), 3.19(1H, m, 1H of BzpipH-2, H-6), 3.12 (1H, m, 1H of BzpipH-2, H-6), 2.08(1H, m, 1H of BzpipH-3, H-5), 1.90 (1H, m, 1H of BzpipH-3, H-5), 1.78(2H, m, 2H of BzpipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −101.1, −116.5, −118.6;m/z: 562 [M+H]⁺ (found [M+H]⁺, 561.1844, C₃₂H₃₅N₅O₃ requires [M+H]⁺561.1744).

Compound 343:6-(4-(2,4-difluorophenoxy)piperidine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3-yl)nicotinamide.¹H nmr (CDCl₃) δ 9.79 (1H, s, NH), 8.92 (1H, m, pyH-6), 8.47 (1H, d, J2.5 Hz, N, O-pyH-6), 8.34 (1H, dd, J 9.0, 2.5 Hz, N, O-pyH-4), 8.08 (1H,dd, J 8.0, 2.0 Hz, pyH-4), 7.36 (1H, d, J 8.0 Hz, pyH-3), 7.11-7.01 (4H,m, C₆H₄F), 6.99-6.92 (2H, m, N, O-pyH-3, 1H of C₆H₃F₂), 6.90-6.76 (2H,m, 2H of C₆H₃F₂), 4.47 (1H, m, PhOpipH-4), 3.92 (2H, m, 2H of PhOpipH-2,H-6), 3.66 (1H, m, 1H of PhOpipH-2, H-6), 3.35 (1H, m, 1H of PhOpipH-2,H-6), 1.98 (2H, m, 2H of PhOpipH-3, H-5), 1.93-1.80 (2H, m, 2H ofPhOpipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −117.4, −118.5, −127.3; m/z: 549[M+H]⁺.

Compound 344:6-(4-(2,4-difluorophenoxy)piperidine-1-carbonyl)-N-(1-(4-methoxybenzyl)piperidin-4-yl)nicotinamide.¹H nmr (CDCl₃) δ 8.91 (1H, m, pyH-6), 8.21 (1H, dd, J 8.0, 2.0 Hz,pyH-4), 7.57 (1H, d, J 8.0 Hz, pyH-3), 7.25 (2H, d, J 9.0 Hz, 2H ofC₆H₄OCH₃), 6.97 (1H, td, J 9.0, 5.5 Hz, 1H of C₆H₃F₂), 6.89-6.75 (4H, m,2H of C₆H₄OCH₃, 2H of C₆H₃F₂), 4.45 (1H, m, PhOpipH-4), 4.03 (1H, m, 1Hof pipH-4), 3.92-3.85 (2H, m, 2H of PhOpipH-2, H-6), 3.79 (3H, s, OCH₃),3.71 (1H, m, 1H of PhOpipH-2, H-6), 3.57 (2H, s, CH ₂C₆H₄OCH₃),3.44-3.37 (1H, m, 1H of PhOpipH-2, H-6), 2.97 (2H, m, 2H of pipH-2,H-6), 2.27 (2H, dd, J 11.5, 10.5 Hz, 2H of pipH-2, H-6), 2.04-1.90 (5H,m, 2H of pipH-3, H-5, 3H of PhOpipH-3, H-5), 1.83 (1H, m, 1H ofPhOpipH-3, H-5), 1.72 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ−117.7, −127.3; m/z: 565 [M+H]⁺.

Compound 345:N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(2,4-difluorophenoxy)piperidine-1-carbonyl)nicotinamide.¹H nmr (CDCl₃) δ 8.90 (1H, m, pyH-6), 8.13 (1H, dd, J 8.0, 2.0 Hz,pyH-4), 7.65 (1H, d, J 8.5 Hz, pyH-3), 7.61 (2H, d, J 8.5 Hz, 2H ofC₆H₄CN), 7.45 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 6.98 (1H, dt, J 5.0, 9.0Hz, 1H of C₆H₃F₂H-5 or H-6), 6.86 (1H, m, 1H of C₆H₃F₂H-3), 6.79 (1H, m,1H of C₆H₃F₂H-5 or H-6), 6.24 (1H, d, J 8.0 Hz, NH), 4.47 (1H, m,PhOpipH-4), 4.03 (1H, m, pipH-4), 3.95-3.87 (2H, m, 2H of PhOpipH-2,H-6), 3.75 (1H, m, 1H of PhOpipH-2, H-6), 3.57 (2H, s, CH ₂C₆H₄CN), 3.42(1H, m, 1H of PhOpipH-2, H-6), 2.84 (2H, m, 2H of pipH-2, H-6), 2.21(2H, dd, J 11.5, 9.5 Hz, 2H of pipH-2, H-6), 2.06-1.92 (5H, m, 2H ofpipH-3, H-5, 3H of PhOpipH-3, H-5), 1.86 (1H, m, 1H of PhOpipH-3, H-5),1.62 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ−117.6, −127.3; m/z:560 [M+H]⁺.

Compound 346:N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(2,4-difluorobenzoyl)piperidine-1-carbonyl)nicotinamide.¹H nmr (CDCl₃) δ 8.89 (1H, m, pyH-6), 8.10 (1H, dd, J 8.5, 2.0 Hz,pyH-4), 7.87 (1H, dt, J 6.5, 8.5 Hz, 1H of C₆H₃F₂), 7.61 (2H, d, J 8.5Hz, 2H of C₆H₄CN), 7.58 (1H, m, pyH-3), 7.45 (2H, d, J 8.0 Hz, 2H ofC₆H₄CN), 6.99 (1H, ddd, J 9.5, 9.0, 2.5 Hz, 1H of C₆H₃F₂), 6.89 (1H, m,1H of C₆H₃F₂), 6.50 (1H, d, J 8.0 Hz, NH), 4.67 (1H, m, 1H of BzpipH-2,H-6), 4.02 (1H, m, pipH-4), 3.89 (1H, m, 1H of BzpipH-2, H-6), 3.56 (3H,s, CH ₂C₆H₄CN), 3.40 (1H, m, BzpipH-4), 3.21 (1H, m, BzpipH-2, H-6),3.08 (1H, ddd, J 11.5, 10.5, 3.0 Hz, 1H of BzpipH-2, H-6), 2.83 (2H, m,2H of pipH-2, H-6), 2.21 (2H, dd, J 11.5, 10.0 Hz, 2H of pipH-2, H-6),2.08-2.01 (3H, m, 2H of pipH-3, H-5, 1H of BzpipH-3, H-5), 1.89-1.72(3H, m, 3H of BzpipH-3, H-5), 1.63 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr(CDCl₃) δ −101.5, −106.5; m/z: 572 [M+H]⁺.

Compound 347:6-(4-(2,4-difluorobenzoyl)piperidine-1-carbonyl)-N-(1-(4-methoxybenzyl)piperidin-4-yl)nicotinamide.¹H nmr (CDCl₃) δ 8.88 (1H, d, J 2.0 Hz, pyH-6), 8.11 (1H, dd, J 8.0, 2.0Hz, pyH-4), 7.86 (1H, dt, J 6.5, 8.5 Hz, 1H of C₆H₃F₂), 7.59 (1H, d, J8.0 Hz, pyH-3), 7.23 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 6.98 (1H, m, 1Hof C₆H₃F₂), 6.92-6.84 (3H, m, 2H of C₆H₄OCH₃, 1H of C₆H₃F₂), 6.39 (1H,d, J 7.5 Hz, NH), 4.65 (1H, m, 1H of BzpipH-2, H-6), 4.01 (1H, m,pipH-4), 3.89 (1H, m, 1H of BzpipH-2, H-6), 3.80 (3H, s, OCH₃), 3.51(2H, s, CH ₂C₆H₄OCH₃), 3.39 (1H, m, BzpipH-4), 3.21 (1H, ddd, J 10.5,9.0, 3.0 Hz, 1H of BzpipH-2, H-6), 3.08 (1H, m, 1H of BzpipH-2, H-6),2.90 (2H, m, 2H of pipH-2, H-6), 2.21 (2H, dd, J 11.5, 10.0 Hz, 2H ofpipH-2, H-6), 2.03 (4H, m, 2H of pipH-3, H-5, 2H of BzpipH-3, H-5),1.89-1.76 (2H, m, 2H of BzpipH-3, H-5), 1.62 (2H, m, 2H of pipH-3, H-5);¹⁹F nmr (CDCl₃) δ −101.6, −106.5; m/z: 577 [M+H]⁺.

Compound 348:6-(4-(2,4-difluorobenzoyl)piperidine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3-yl)nicotinamide.¹H nmr (CDCl₃) δ 9.81 (1H, s, NH), 8.91 (1H, m, pyH-6), 8.48 (1H, d, J2.5 Hz, N,O-pyH-6), 8.34 (1H, dd, J 8.5, 2.5 Hz, N,O-pyH-4), 8.07 (1H,dd, J 8.0, 2.0 Hz, pyH-4), 7.87 (1H, dt, J 8.5, 6.5 Hz, 1H of C₆H₃F₂),7.35 (1H, d, J 8.0 Hz, pyH-3), 7.10-6.85 (3H, m, N,O-pyH-3, 2H ofC₆H₃F₂), 4.65 (1H, m, 1H of BzpipH-2, H-6), 3.78-3.73 (1H, m, 1H ofBzpipH-2, H-6), 3.40 (1H, m, BzpipH-4), 3.23-3.07 (2H, m, 2H ofBzpipH-2, H-6), 2.08 (1H, m, 1H of BzpipH-3, H-5), 1.90-1.74 (3H, m, 3Hof BzpipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −101.3, −106.5, −118.6; m/z: 561[M+H]⁺.

Synthesis of Compounds 349 and 350 Coupling of the1-tert-Butyloxycarbonyl-3-Fluoro-4-aminopiperidine

To a mixture of the crude pyridine carboxylic acid (2.15 g ofapproximately 66% purity, 3.86 mmol, 1.0 eq) and1-tert-butyl-3-fluoro-4-aminopiperidine (0.84 g, 3.86 mmol, 1.0 eq) wasadded dimethylformamide (40 mL) followed by triethylamine (1.31 mL, 9.64mmol, 2.5 eq). After the addition of HATU (1.47 g, 3.86 mmol, 1.0 eq)the reaction was stirred at room temperature for 4 hours beforepartitioning between EtoAc (300 mL) and water-NaHCO₃ (1:1, 300 mL). Theorganics were further washed with brine (250 mL), water (300 mL) andbrine (250 mL) before drying (Na₂SO₄) and concentrating under reducedpressure. MPLC (0→10% MeOH—CH₂Cl₂) yielded the coupled material (1.41 g,64%) as a pale yellow oil; ¹H nmr (CDCl₃) δ 8.90 (1H, m, pyH-6), 8.11(1H, dt, J 8.0, 2.0 Hz, pyH-4), 7.93 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃),7.56 (1H, d, J 6.0 Hz, NH), 7.50 (1H, dd, J 8.0, 2.0 Hz, pyH-3), 6.95(2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 4.65 (1H, m, 1H of BzpipH-2, H-6),4.47 (0.5H, m, 0.5H of pipH-3), 4.31 (2.5H, m, 0.5H of pipH-3, pipH-4,1H of pipH-2), 4.00 (1H, m, 1H of BzpipH-2, H-6), 3.87 (3H, s, OCH₃),3.84 (1H, m, 1H of pipH-6), 3.53 (1H, m, BzpipH-4), 3.23 (1H, m, 1H ofpipH-6), 3.11 (1H, m, 1H of BzpipH-2, H-6), 2.90 (2H, m, 1H of pipH-2,1H of BzpipH-2, H-6), 2.08-1.92 (2H, m, 2H of pipH-5, BzpipH-3, H-5),1.91-1.80 (4H, m, 4H of pipH-5, BzpipH-3, H-5), 1.47 (9H, s, C(CH₃)₃);¹⁹F nmr (CDCl₃) δ −189.3 (d, J 47.5 Hz); m/z: 569 [M+H]⁺.

Deprotection of the Tert-Butyloxycarbonyl Group

To a solution of the tert-butyloxycarbonylpiperidine (1.41 g, 2.48 mmol,1.0 eq) in dichloromethane (25 mL) was added hydrogen chloride (2.5 mLof a 4.0M solution in dioxane, 9.93 mmol, 4.0 eq). The reaction wasstirred at room temperature for 6 hours. A residue formed over thecourse of the reaction. Et₂O (100 mL) was added resulting in apercipitate after sonication, which was isolated by filtration. Theresulting solid was dried under vacuum to yield the fluoropiperidinedihydrochloride as a pale orange solid (1.32 g, quantitative), which wasused without further purification; ¹H nmr (D₆-DMSO) δ 8.96 (2H, m, CONH,pyH-6), 8.30 (1H, dt, J 8.0, 2.0 Hz, pyH-4), 7.94 (2H, d, J 9.0 Hz, 2Hof C₆ H ₄OCH₃), 7.62 (1H, dd, J 8.0 Hz, pyH-3), 6.99 (2H, d, J 9.5 Hz,2H of C₆ H ₄OCH₃), 4.93, 4.75 (1H, 2 m, pipH-3), 4.46 (1H, m, 1H ofBzpipH-2, H-6), 4.32 (1H, m, pipH-4), 3.78 (3H, s, OCH₃), 3.69 (1H, m,BzpipH-4), 3.57-3.50 (2H, m, 1H of pipH-2, 1H of BzpipH-2, H-6),3.28-3.10 (3H, m, 1H of pipH-2, 1H of pipH-6, 1H of BzpipH-2, H-6),3.08-2.94 (2H, m, 1H of pipH-6, 1H of BzpipH-2, H-6), 2.02 (1H, m, 1H ofpipH-5), 1.82 (2H, m, 1H of pipH-5, 1H of BzpipH-3, H-5), 1.63 (1H, m,1H of BzpipH-3, H-5), 1.55-1.47 (2H, m, 2H of BzpipH-3, H-5); ¹⁹F nmr(D₆-DMSO) δ −188.6 (d, J 50.0 Hz); m/z: 469 [M+H]⁺.

Compound 349

To a suspension of the fluoropiperidine dihydrochloride (0.250 g, 0.462mmol, 1.0 eq) in dischlormethane (5.0 mL) was addeddiisopropylethylamine (0.28 mL, 1.617 mmol, 3.5 eq) to form a clearsolution. 4-Cyanobenzyl bromide (0.100 g, 0.508 mmol, 1.1 eq) was addedand the reaction stirred at room temperature for 5 hours before pouringinto NaHCO₃ (40 mL). The organics were extracted with CH₂Cl₂ (3×40 mL),combined, dried (Na₂SO₄) and concentrated under reduced pressure. MPLC(3→5% MeOH—CH₂Cl₂) yielded the cyanobenzylpiperidine (0.162 g, 60%) as awhite foam; IR (film) 3313, 2953, 1662, 1622, 1599, 1544, 1448, 1259,1170, 1027, 971, 912, 848, 731 cm⁻¹; ¹H nmr (CDCl₃) δ 8.88 (1H, d, J 2.0Hz, pyH-6), 8.07 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.94 (2H, d, J 9.0 Hz,2H of C₆H₄OCH₃), 7.60 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.48 (1H, d, J8.0 Hz, pyH-3), 7.43 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.33 (1H, m, NH),6.96 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 4.70 (1H, m, 1H of BzpipH-2,H-6), 4.70, 4.53 (1H, m, pipH-3), 4.15 (1H, m, pipH-4), 3.88 (3H, s,OCH₃), 3.82 (1H, m, 1H of BzpipH-2, H-6), 3.63 (2H, s, CH ₂C₆H₄CN), 3.54(1H, m, BzpipH-4), 3.28-3.09 (3H, m, 2H of BzpipH-2, H-6, 1H of pipH-6),2.80 (1H, m, 1H of pipH-2), 2.30-2.17 (3H, m, 1H of pipH-6, 1H ofpipH-5, 1H of pipH-2), 2.03 (1H, m, 1H of BzpipH-3, H-5), 1.93-1.82 (3H,m, 3H of BzpipH-3, H-5), 1.67 (1H, m, 1H of pipH-5); ¹³C nmr (CDCl₃) δ199.9, 167.2, 165.3, 163.7, 155.8, 147.5, 143.8, 136.1, 132.2, 130.8,130.6, 129.2, 128.5, 122.6, 118.8, 114.0, 111.1, 89.5 (90.7, 88.4, d, J178.5 Hz), 61.7, 56.5 (56.7, 56.3, J 25.0 Hz), 55.5, 52.3 (52.4, 52.1, J17.5 Hz), 51.7, 46.7, 42.6, 41.9, 29.9 (29.9, 29.8 J 6.5 Hz), 28.6(28.8, 28.4, J 28.0 Hz); ¹⁹F nmr (CDCl₃) δ −188.5 (d, J 55 Hz); m/z: 584[M+H]⁺ (found [M+H]⁺, 584.2711, C₃₃H₃₄FN₅O₄ requires [M+H]⁺ 584.2668).Compound 350

To a suspension of the fluoropiperidine dihydrochloride (0.100 g, 0.185mmol, 1.0 eq) in dichloromethane (2.0 mL) was addeddiisopropylethylamine (0.112 mL, 0.647 mmol, 3.5 eq) forming a clearsolution. Trifluoromethoxybenzyl bromide (0.035 mL, 0.218 mmol, 1.2 eq)was added and the reaction stirred at room temperature for 4 hoursbefore pouring into NaHCO₃ (50 mL). The organics were extracted withCH₂Cl₂ (3×45 mL), combined, dried (Na₂SO₄), and concentrated underreduced pressure. MPLC (0→10% MeOH—CH₂Cl₂) yielded thetrifluoromethoxypiperidine (0.076 g, 64%) as a white foam; IR (film)3314, 3074, 2953, 1665, 1623, 1600, 1509, 1449, 1260, 1221, 1169, 1028,971, 732 cm⁻¹; ¹H nmr (CDCl₃) δ 8.88 (1H, d, J 2.0 Hz, pyH-6), 8.07 (1H,dd, J 8.0, 2.0 Hz, pyH-4), 7.94 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 7.48(1H, d, J 8.5 Hz, pyH-3), 7.33 (2H, d, J 8.5 Hz, 2H of C₆H₄OCF₃), 7.15(2H, d, J 8.0 Hz, 2H of C₆H₄OCF₃), 6.95 (2H, d, J 9.0 Hz, 2H ofC₆H₄OCH₃), 4.69 (1H, m, 1H of BzpipH-2, H-6), 4.69, 4.52 (1H, m,pipH-3), 4.15 (1H, m, pipH-4), 3.87 (3H, s, OCH₃), 3.82 (1H, m, 1H ofBzpipH-2, H-6), 3.58-3.50 (3H, m, CH ₂C₆H₄OCF₃, BzpipH-4), 3.28-3.08(3H, m, 2H of BzpipH-2, H-6, 1H of pipH-2 or H-6), 2.82 (1H, m, 1H ofpipH-2 or H-6), 2.26-2.14 (3H, m, 1H of pipH-5, 2H of pipH-2, H-6), 2.01(1H, m, 1H of BzpipH-3, H-5), 1.94-1.80 (3H, m, 3H of BzpipH-3, H-5),1.66 (1H, m, 1H of pipH-5); ¹³C nmr (CDCl₃) δ 200.0, 167.2, 165.3,163.7, 155.8, 148.4, 147.4, 136.7, 136.1, 130.8, 130.0, 128.5, 122.7,120.9, 114.0, 89.7 (90.9, 88.6 J 178.5 Hz), 61.4, 56.3 (56.5, 56.2 J25.4 Hz), 55.5, 52.4 (52.5, 52.3 J 18.2 Hz), 51.6, 46.7, 42.6, 41.9,29.9 (30.0, 29.9 J 6.6 Hz), 28.6 (28.8, 28.4 J 17.7 Hz); ¹⁹F nmr (CDCl₃)δ −57.9, −188.4; m/z: 644 [M+H]⁺ (found [M+H]⁺, 643.2534, C₃₃H₃₄F₄N₄O₅requires [M+H]⁺ 643.2538).

Compound 349:N-((trans)-1-(4-cyanobenzyl)-3-fluoropiperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide.¹H nmr (CDCl₃) δ 8.88 (1H, d, J 2.0 Hz, pyH-4), 8.07 (1H, dd, J 8.5, 2.0Hz, pyH-4), 7.94 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 7.60 (2H, d, J 8.0Hz, 2H of C₆H₄CN), 7.48 (1H, d, J 8.0 Hz, pyH-3), 7.43 (2H, d, J 8.0 Hz,2H of C₆H₄CN), 7.33 (1H, m, NH), 6.96 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃),4.70 (1H, m, 1H of BzpipH-2, H-6), 4.70, 4.53 (1H, m, pipH-3), 4.15 (1H,m, pipH-4), 3.88 (3H, s, OCH₃), 3.82 (1H, m, 1H of BzpipH-2, H-6), 3.63(2H, s, CH ₂C₆H₄CN), 3.54 (1H, m, BzpipH-4), 3.28-3.09 (3H, m, 2H ofBzpipH-2, H-6, 1H of pipH-6), 2.80 (1H, m, 1H of pipH-2), 2.30-2.17 (3H,m, 1H of pipH-6, 1H of pipH-5, 1H of pipH-2), 2.03 (1H, m, 1H ofBzpipH-3, H-5), 1.93-1.82 (3H, m, 3H of BzpipH-3, H-5), 1.67 (1H, m, 1Hof pipH-5); ¹⁹F nmr (CDCl₃) δ−188.5; m/z: 584 [M+H]⁺.

Compound 350:N-((trans)-3-fluoro-1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide.¹H nmr (CDCl₃) δ 8.88 (1H, d, J 2.0 Hz, pyH-6), 8.07 (1H, dd, J 8.0, 2.0Hz, pyH-4), 7.94 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 7.48 (1H, d, J 8.5Hz, pyH-3), 7.33 (2H, d, J 8.5 Hz, 2H of C₆H₄OCF₃), 7.15 (2H, d, J 8.0Hz, 2H of C₆H₄OCF₃), 6.95 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 4.69 (1H,m, 1H of BzpipH-2, H-6), 4.69, 4.52 (1H, m, pipH-3), 4.15 (1H, m,pipH-4), 3.87 (3H, s, OCH₃), 3.82 (1H, m, 1H of BzpipH-2, H-6),3.58-3.50 (3H, m, CH ₂C₆H₄OCF₃, BzpipH-4), 3.28-3.08 (3H, m, 2H ofBzpipH-2, H-6, 1H of pipH-2 or H-6), 2.82 (1H, m, 1H of pipH-2 or H-6),2.26-2.14 (3H, m, 1H of pipH-5, 2H of pipH-2, H-6), 2.01 (1H, m, 1H ofBzpipH-3, H-5), 1.94-1.80 (3H, m, 3H of BzpipH-3, H-5), 1.66 (1H, m, 1Hof pipH-5); ¹⁹F nmr (CDCl₃) δ −57.9, −188.4; m/z: 644 [M+H]⁺.]

Compound 351:N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(4-cyanophenoxy)piperidin-1-yl)pyridazine-3-carboxamide.¹H nmr (CDCl₃) δ 8.01 (1H, d, J 9.0 Hz, pzH-4 or H-5), 7.86 (1H, d, J8.5 Hz, NH), 7.62 (2H, d, J 8.0 Hz, 2H of OC₆H₄CN), 7.61 (2H, d, J 9.0Hz, 2H of CH₂C₆ H ₄CN), 7.45 (2H, d, J 8.5 Hz, 2H of CH₂C₆ H ₄CN), 7.02(1H, d, J 10.0 Hz, pzH-4 or H-5), 6.97 (2H, d, J 9.0 Hz, 2H of OC₆H₄CN),4.72 (1H, m, PhOpipH-4), 3.98 (3H, m, 2H of PhOpipH-2, H-6, pipH-4),3.86-3.78 (2H, m, 2H of PhOpipH-2, H-6), 3.55 (2H, s, CH ₂C₆H₄CN), 2.80(2H, m, 2H of pipH-2, H-6), 2.22 (dd, J 11.0, 9.0 Hz, 2H of pipH-2,H-6), 2.13-1.93 (6H, m, PhOpipH-3, H-5, 2H of pipH-3, H-5), 1.61 (1H, m,pipH-5); m/z: 522 [M+H]⁺.

Compound 352:N-((trans)-3-fluoro-1-(4-(pyrrolidin-1-yl)benzyl)piperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide.¹H nmr (CDCl₃) δ 8.89 (1H, m, pyH-6), 8.09 (1H, dd, J 8.0, 2.0 Hz,pyH-4), 7.94 (2H, d, J 8.5 Hz, 2H of C₆H₄OCH₃), 7.52 (1H, d, J 8.0 Hz,pyH-3), 7.13 (2H, d, J 9.0 Hz, 2H of C₆H₄N), 7.03 (1H, d, J 8.0 Hz, NH),6.95 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 6.51 (2H, d, J 9.0 Hz, 2H ofC₆H₄N), 4.68 (1H, m, 1H of BzpipH-2, H-6), 4.65, 4.48 (1H, m, pipH-3),4.13 (1H, m, pipH-4), 3.87 (4H, m, OCH₃, 1H of BzpipH-2, H-6), 3.54-3.47(3H, m, NCH ₂C₆H₄N, BzpipH-4), 3.26 (6H, m, 4H of pyrrolidine, 1H ofBzpipH-2, H-6, 1H of pipH-6), 3.11 (1H, m, 1H of BzpipH-2, H-6), 2.84(1H, d, J 11.5 Hz, 1H of pipH-2), 2.19-2.12 (3H, m, 1H of pipH-2, H-5,H-6), 2.08-1.97 (5H, m, 4H of pyrrolodine, 1H of BzpipH-3, H-5),2.94-1.80 (3H, m, 3H of BzpipH-3, H-5), 1.61 (1H, 1H of pipH-5); ¹⁹F nmr(CDCl₃) δ −188.4; m/z: 528 [M+H]⁺.

Compound 353:N-((trans)-3-fluoro-1-(4-isopropoxybenzyl)piperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide.¹H nmr (CDCl₃) δ 8.88 (1H, m, pyH-6), 8.07 (1H, dd, J 8.0, 2.0 Hz,pyH-4), 7.94 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 7.50 (1H, d, J 8.0 Hz,pyH-3), 7.18 (2H, d, J 8.5 Hz, 2H of C₆H₄OiPr), 7.15 (1H, m, NH), 6.95(2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 6.83 (2H, d, J 8.5 Hz, 2H ofC₆H₄OiPr), 4.67 (1H, m, 1H of BzpipH-2, H-6), 4.67, 4.50 (1H, m,pipH-3), 4.52 (1H, m, OCH(CH₃)₂), 4.03 (1H, m, pipH-4), 3.87 (3H, s,OCH₃), 3.83 (1H, m, 1H of BzpipH-2, H-6), 3.54, 3.47 (2H, d AB system, J13.0 Hz, CH ₂C₆H₄O), 3.52 (1H, m, BzpipH-4), 3.22 (2H, m, 1H ofBzpipH-2, H-6, 1H of pipH-6), 3.11 (1H, m, 1H of BzpipH-2, H-6), 2.83(1H, d, J 11.0 Hz, 1H of pipH-2), 2.21-2.10 (3H, 1H of pipH-2, H-5,H-6), 2.02 (1H, m, 1H of BzpipH-3, H-5), 1.93-1.76 (3H, m, 3H ofBzpipH-3, H-5), 1.63 (1H, m, 1H of pipH-5); ¹⁹F nmr (CDCl₃) δ −188.4;m/z: 617 [M+H]⁺.

Compound 354:N-((trans)-1-(4-cyano-3-fluorobenzyl)-3-fluoropiperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide.¹H nmr (CDCl₃) δ 8.88 (1H, m, pyH-6), 8.07 (1H, dd, J 8.0, 2.0 Hz,pyH-4), 7.94 (2H, d, J 8.5 Hz, 2H of C₆H₄OCH₃), 7.57 (1H, dd, J 7.5, 6.5Hz, 1H of C₆H₃FCN), 7.49 (1H, d, J 8.0 Hz, pyH-3), 7.30 (1H, d, J 7.0Hz, NH), 7.23 (2H, m, 2H of C₆H₃FCN), 6.96 (2H, d, J 9.0 Hz, 2H ofC₆H₄OCH₃), 4.71 (1H, m, 1H of BzpipH-2, H-6), 4.71, 4.54 (1H, m,pipH-3), 4.17 (1H, m, pipH-4), 3.88 (3H, s, OCH₃), 3.83 (1H, m, 1H ofBzpipH-2, H-6), 3.63 (2H, s, CH₂C₆H₃FCN), 3.54 (1H, m, BzpipH-4),3.28-3.09 (3H, 2H of BzpipH-2, H-6, 1H of pipH-2, H-6), 2.80 (1H, m, 1Hof pipH-2, H-6), 2.33-2.17 (3H, m, pipH-2, H-3, H-6), 2.03 (1H, m, 1H ofBzpipH-3, H-5), 1.93-1.81 (3H, m, 3H of BzpipH-3, H-5), 1.68 (1H, m,pipH-5); ¹⁹F nmr (CDCl₃) δ −106.6, −188.5; m/z: 602 [M+H]⁺(found [M+H]⁺,602.2589, C₃₃H₃₃F₂N₅O₄ requires [M+H]⁺ 602.2813).

Compound 355:6-(4-(4-cyanophenoxy)piperidine-1-carbonyl)-N-(1-(oxazol-4-ylmethyl)piperidin-4-yl)nicotinamide.¹H nmr (CDCl₃) δ 8.91 (1H, m, pyH-6), 8.15 (1H, dd, J 8.0, 2.0 Hz,pyH-4), 7.86 (1H, d, J 1.0 Hz, 1H of oxazole), 7.61-7.26 (3H, m, 2H ofC₆H₄CN, 1H of oxazole), 6.96 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 6.18 (1H,d, J 7.5 Hz, NH), 4.70 (1H, m, PhOpipH-4), 4.02 (1H, m, pipH-4), 3.91(2H, m, 2H of PhOpipH-2, H-6), 3.72 (1H, m, 1H of PhOpipH-2, H-6), 3.53(2H, s, CH₂oxazole), 3.50 (1H, m, 1H of PhOpipH-2, H-6), 2.96 (2H, m, 2Hof pipH-2, H-6), 2.26 (2H, dd, J 11.5, 9.5 Hz, 2H of pipH-2, H-6),2.07-1.99 (5H, m, 2H of pipH-3, H-5, 3H of PhOpipH-3, H-5), 1.88 (1H, m,1H of PhOpipH-3, H-5), 1.63 (2H, m, 2H of pipH-3, H-5); m/z: 516 [M+H]⁺.

Compound 356:6-(4-(4-cyanophenoxy)piperidine-1-carbonyl)-N-(1-(thiazol-2-ylmethyl)piperidin-4-yl)nicotinamide.¹H nmr (CDCl₃) δ 8.91 (1H, m, pyH-6), 8.12 (1H, dd, J 8.5, 2.0 Hz,pyH-4), 7.71 (1H, dd, J 6.5, 2.0 Hz, 1H of thiophene), 7.58 (3H, m,pyH-3, 2H of C₆H₄CN), 7.27 (1H, dd, J 6.5, 3.5 Hz, 1H of thiophene),6.96 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 6.56 (1H, d, J 7.5 Hz, NH), 4.70(1H, m, PhOpipH-4), 4.05-3.91 (3H, m, pipH-4, 2H of PhOpipH-2, H-6),3.89 (2H, s, CH₂thiophene), 3.69 (1H, m, 1H of PhOpipH-2, H-6), 3.52(1H, m, 1H of PhOpipH-2, H-6), 2.97 (2H, m, 2H of pipH-2, H-6), 2.37(2H, t, J 11.5 Hz, 2H of pipH-2, H-6), 2.04 (5H, m, 2H of pipH-3, H-5,3H of PhOpipH-3, H-5), 1.87 (1H, m, 1H of PhOpipH-3, H-5), 1.67 (2H, m,2H of pipH-3, H-5); m/z: 531 [M+H]⁺.

Compound 357:N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-(dimethylcarbamoyl)phenoxy)piperidine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 8.60 (1H, m, pyH-6), 8.24 (1H, d, J 8.0 Hz, pyH-3),7.92 (1H, d, J 8.0 Hz, NH), 7.89 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.61(2H, d, J 8.5 Hz, 2H of 2H of C₆H₄CN), 7.47 (2H, d, J 8.5 Hz, 2H ofC₆H₄CN), 7.40 (2H, d, J 9.0 Hz, 2H of C₆H₄CON(CH₃)₂), 6.91 (2H, d, J 9.0Hz, 2H of C₆H₄CON(CH₃)₂), 4.66 (1H, m, PhOpipH-4), 4.01 (1H, m, pipH-4),3.90 (2H, m, 2H of PhOpipH-2, H-6), 3.64 (1H, m, 1H of PhOpipH-2, H-6),3.57 (2H, s, CH ₂C₆H₄CN), 3.38 (1H, m, 1H of PhOpipH-2, H-6), 3.05 (6H,s, N(CH₃)₂), 2.82 (2H, m, 2H of pipH-2, H-6), 2.24 (2H, dd, J 10.5, 10.0Hz, 2H of pipH-2, H-6), 2.20 (4H, m, 2H of pipH-3, H-5, 2H of PhOpipH-3,H-5), 1.87 (2H, m, 2H of PhOpipH-3, H-5), 1.65 (2H, m, 2H of pipH-3,H-5); m/z: 595 [M+H]⁺.

Compound 358:5-(4-(4-acetylphenoxy)piperidine-1-carbonyl)-N-(1-(4-cyanobenzyl)piperidin-4-yl)picolinamide.¹H nmr (CDCl₃) δ 8.61 (1H, d, J 2.0 Hz, pyH-6), 8.25 (1H, d, J 8.5 Hz,pyH-3), 7.94 (2H, d, J 9.5 Hz, 2H of C₆H₄COCH₃), 7.90 (1H, m, NH), 7.89(1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.61 (2H, d, J 8.5 Hz, 2H of C₆H₄CN),7.45 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 6.95 (2H, d, J 8.5 Hz, 2H ofC₆H₄COCH₃), 4.73 (1H, m, PhOpipH-4), 4.01 (1H, m, pipH-4), 4.00-76 (2H,m, 2H of PhOpipH-2, H-6), 3.63 (1H, m, 1H of PhOpipH-2, H-6), 3.57 (2H,s, CH ₂C₆H₄CN), 3.40 (1H, m, 1H of PhOpipH-2, H-6), 2.82 (2H, m, 2H ofpipH-2, H-6), 2.55 (3H, s, COCH₃), 2.23 (2H, dd, J 11.0, 10.0 Hz, 2H ofpipH-2, H-6), 2.04-1.91 (6H, m, 2H of pipH-3, H-5, PhOpipH-3, H-5), 1.65(2H, m, 2H of pipH-3, H-5); m/z: 566 [M+H]⁺.

Compound 359:5-(4-(4-acetylphenoxy)piperidine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3-yl)picolinamide.¹H nmr (CDCl₃) δ 9.89 (1H, s, NH), 8.68 (1H, d, J 2.0 Hz, pyH-6), 8.41(1H, 2.5 Hz, N,O-pyH-6), 8.34 (2H, m, pyH-3, N,O-pyH-4), 7.96 (1H, dd, J8.0, 2.0 Hz, pyH-4), 7.94 (2H, d, J 9.0 Hz, 2H of C₆H₄COCH₃), 7.09 (4H,m, C₆H₄F), 6.95 (3H, m, 2H of C₆H₄COCH₃, N,O-pyH-3), 4.75 (1H, m,PhOpipH-4), 3.98 (1H, m, 1H of PhOpipH-2, H-6), 3.87 (1H, m, 1H ofPhOpipH-2, H-6), 3.68 (1H, m, 1H of PhOpipH-2, H-6), 3.42 (1H, m, 1H ofPhOpipH-2, H-6), 2.56 (3H, s, COCH₃), 2.04-1.93 (4H, m, PhOpipH-3, H-5);m/z: 555 [M+H]⁺.

Compound 360:5-(4-(4-(dimethylcarbamoyl)phenoxy)piperidine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3-yl)picolinamide.¹H nmr (CDCl₃) δ 8.90 (1H, s, NH), 8.69 (1H, m, pyH-6), 8.41 (1H, d, J3.0 Hz, N,O-pyH-6), 8.35 (2H, m, pyH-3, N,O-pyH-4), 7.96 (1H, dd, J 8.0,2.0 Hz, pyH-4), 7.40 (2H, d, J 9.0 Hz, 2H of C₆H₄CON(CH₃)₂), 7.10 (4H,m, C₆H₄F), 6.97 (1H, d, J 9.0 Hz, N,O-pyH-3), 6.92 (2H, d, J 9.0 Hz, 2Hof C₆H₄CON(CH₃)₂), 4.68 (1H, m, PhOpipH-4), 3.95 (1H, m, 2H ofPhOpipH-2, H-6), 3.89 (1H, m, 2H of PhOpipH-2, H-6), 3.66 (1H, m, 2H ofPhOpipH-2, H-6), 3.41 (1H, m, 2H of PhOpipH-2, H-6), 3.06 (6H, s,N(CH₃)₂), 2.02 (2H, m, 2H of PhOpipH-3, H-5), 1.91 (2H, m, 2H ofPhOpipH-3, H-5; ¹⁹F nmr (CDCl₃) δ −118.5; m/z: 584 [M+H]⁺.

Compound 361:N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)pyridazine-3-carboxamide.¹H nmr (CDCl₃) δ 8.00 (1H, d, J 9.5 Hz, pyH-4 or H-5), 7.87 (1H, d, J8.0 Hz, NH), 7.61 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.56 (2H, d, J 9.0Hz, 2H of C₆H₄CF₃), 7.45 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.01 (2H, d, J8.5 Hz, pyH-4 or H-5), 7.00 (2H, d, J 9.0 Hz, 2H of C₆H₄CF₃), 4.71 (1H,m, PhOpipH-4), 4.03-3.94 (3H, m, pipH-4, 2H of PhOpipH-2, H-6),3.86-3.78 (2H, m, 2H of PhOpipH-2, H-6), 3.55 (2H, s, CH₂C₆H₄CN), 2.79(2H, m, 2H of pipH-2, H-6), 2.22 (2H, dd, J 11.0, 10.0 Hz, 2H of pipH-2,H-6), 2.12-1.93 (6H, m, 2H of pipH-3, H-5, PhOpipH-3, H-5), 1.64 (2H, m,2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −61.6; m/z: 565 [M+H]⁺ (found[M+H]⁺, 565.2567, C₃₀H₃₁F₃N₆O₂ requires [M+H]⁺ 565.2533).

Compound 362:N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidin-1-yl)pyridazine-3-carboxamide.¹H nmr (CDCl₃) δ 7.99 (1H, d, J 9.5 Hz, pyH-4 or H-5), 7.96 (2H, d, J9.0 Hz, 2H of C₆H₄OCH₃), 7.87 (1H, d, J 8.5 Hz, NH), 7.61 (2H, d, J 8.0Hz, 2H of C₆H₄CN), 7.45 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.00 (1H, m,pyH-4 or H-5), 6.97 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 4.52 (2H, m, 2Hof BzpipH-2, H-6), 4.01 (1H, m, pipH-4), 3.89 (3H, s, OCH₃), 3.58 (1H,m, BzpipH-4), 3.55 (2H, s, CH₂C₆H₄CN), 3.28 (2H, m, 2H of BzpipH-2,H-6), 2.79 (2H, m, 2H of pipH-2, H-6), 2.23 (2H, dd, J 11.0, 9.0 Hz, 2Hof pipH-2, H-6), 2.03-1.87 (6H, m, 2H of pipH-3, H-5, BzpipH-3, H-5)1.63 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −61.6, −114.9; m/z:539 [M+H]⁺ (found [M+H]⁺, 539.2782, C₃₁H₃₄N₆O₃ requires [M+H]⁺539.2765).

Compound 363:N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(4-nitrophenoxy)piperidine-1-carbonyl)nicotinamide.¹H nmr (CDCl₃) δ 8.90 (1H, m, pyH-6), 8.20 (2H, d, J 9.0 Hz, 2H ofC₆H₄NO₂), 8.12 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.62 (1H, d, J 8.0 Hz,pyH-3), 7.60 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.44 (2H, d, J 8.0 Hz, 2Hof C₆H₄CN), 6.97 (2H, d, J 9.5 Hz, 2H of C₆H₄NO₂), 6.44 (1H, d, J 8.0Hz, NH), 4.75 (1H, heptet, J 3.0 Hz, PhOpipH-3), 4.00 (1H, m, pipH-4),3.92 (2H, m, 2H of PhOpipH-2, H-6), 3.72 (1H, m, 1H of PhOpipH-2, H-6),3.56 (2H, s, CH ₂C₆H₄CN), 3.51 (1H, m, 1H of PhOpipH-2, H-6), 2.83 (2H,m, 2H of pipH-2, H-6), 2.20 (2H, t, J 11.5 Hz, 2H of pipH-2, H-6),2.12-2.00 (5H, m, 2H of pipH-3, H-5, 3H of PhOpipH-3, H-5), 1.90 (1H, m,1H of PhOpipH-3, H-5), 1.61 (2H, m, 2H of pipH-3, H-5); m/z: 569 [M+H]⁺.

Compound 364:6-(4-(4-aminophenoxy)piperidine-1-carbonyl)-N-(1-(4-cyanobenzyl)piperidin-4-yl)nicotinamide.¹H nmr (CD₃OD) δ 8.90 (1H, m, pyH-6), 8.33 (1H, dd, J 8.5, 2.0 Hz,pyH-4), 7.80 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.70 (2H, d, J 9.0 Hz, 2Hof C₆H₄CN), 7.67 (1H, d, J 9.0 Hz, pyH-3), 6.84 (4H, s, C₆ H ₄NH₂), 4.53(1H, m, PhOpipH-4), 4.15 (2H, s, CH ₂C₆H₄NH₂), 4.10 (1H, m, 1H ofPhOpipH-2, H-6), 3.97 (1H, m, 1H of PhOpipH-2, H-6), 3.77 (1H, m, 1H ofPhOpipH-2, H-6), 3.63 (1H, m, 1H of PhOpipH-2, H-6), 3.37 (2H, m, 2H ofpipH-2, H-6), 2.86 (2H, dd, J 11.5, 12.0 Hz, 2H of pipH-2, H-6), 2.13(2H, m, 2H of PhOpipH-3, H-5 or pipH-3, H-5), 2.04-1.73 (6H, m, 2H or 4Hof pipH-3, H-5, 2H or 4H of PhOpipH-3, H-5); m/z: 539 [M+H]⁺.

Compound 365:N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-(pyrrolidin-1-yl)benzoyl)piperidine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 8.60 (1H, m, pyH-6), 8.23 (1H, d, J 8.0 Hz, pyH-3),7.94 (1H, d, J 8.5 Hz, NH), 7.88 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.86(2H, d, J 9.0 Hz, 2H of C₆H₄N), 7.61 (2H, d, J 8.5 Hz, 2H of C₆H₄CN),7.46 (2H, d, J 8.0 Hz, C₆H₄CN), 6.53 (2H, d, J 9.0 Hz, 2H of C₆H₄N),4.66 (1H, m, 1H of BzpipH-2, H-6), 4.01 (1H, m, pipH-4), 3.73 (1H, m, 1Hof BzpipH-2, H-6), 3.56 (2H, s, CH ₂C₆H₄CN), 3.51 (1H, m, BzpipH-4),3.37 (4H, m, 4H of pyrrolidine), 3.21-3.13 (2H, m, 2H of BzpipH-2, H-6),2.80 (2H, m, 2H of pipH-2, H-6), 2.23 (2H, dd, J 11.5, 9.5 Hz, pipH-2,H-6), 2.06-2.00 (7H, m, 4H of pyrrolidine, 2H of pipH-3, H-5, 1H ofBzpipH-3, H-5), 1.91-1.80 (3H, m, 3H of BzpipH-3, H-5), 1.65 (2H, m, 2Hof pipH-3, H-5); m/z: 605 [M+H]⁺.

Compound 366:6-(4-(4-acetamidophenoxy)piperidine-1-carbonyl)-N-(1-(4-cyanobenzyl)piperidin-4-yl)nicotinamide.¹H nmr (CDCl₃) δ 8.91 (1H, m, pyH-6), 8.14 (1H, dd, J 8.0, 2.5 Hz,pyH-4), 7.63 (1H, m, pyH-3), 7.60 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.46(2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.39 (2H, d, J 9.0 Hz, 2H of C₆H₄NHAc),7.15 (1H, s, NHAc), 6.88 (2H, d, J 9.0 Hz, 2H of C₆H₄NHAc), 6.31 (1H, d,J 8.5 Hz, NHCO), 4.56 (1H, m, PhOpipH-4), 4.03 (1H, m, pipH-4), 3.89(2H, m, 2H of PhOpipH-2, H-6), 3.70 (1H, m, 1H of PhOpipH-2, H-6), 3.58(2H, s, CH ₂C₆H₄CN), 3.48-3.42 (1H, m, 1H of PhOpipH-2, H-6), 2.85 (2H,m, 2H of pipH-2, H-6), 2.22 (2H, dd, J 11.5, 9.0 Hz, 2H of pipH-2, H-6),2.15 (3H, s, COCH₃), 2.08-1.92 (6H, m, 2H of pipH-3, H-5, PhOpipH-3,H-5), 1.67 (2H, m, 2H of pipH-3, H-5); m/z: 581 [M+H]⁺.

Compound 367:N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(4-(methylsulfonamido)phenoxy)piperidine-1-carbonyl)nicotinamide.¹H nmr (CDCl₃) δ 8.91 (1H, m, pyH-6), 8.14 (1H, dd, J 8.0, 2.0 Hz,pyH-4), 7.64 (1H, d, J 8.5 Hz, pyH-3), 7.60 (2H, d, J 8.5 Hz, 2H ofC₆H₄CN), 7.45 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.20 (2H, d, J 9.0 Hz, 2Hof C₆H₄NHMs), 6.90 (2H, d, J 9.0 Hz, C₆H₄NHMs), 6.31 (1H, d, J 8.5 Hz,NHCO), 4.78 (1H, m, PhOpipH-4), 4.03 (1H, m, pipH-4), 3.90 (2H, m, 2H ofPhOpipH-2, H-6), 3.71 (1H, m, 1H of PhOpipH-2, H-6), 3.56 (2H, s,CH₂C₆H₄CN), 3.46 (1H, m, 1H of PhOpipH-2, H-6), 2.96 (3H, s, SO₂CH₃),2.83 (2H, m, 2H of pipH-2, H-6), 2.21 (2H, t, J 11.5 Hz, 2H of pipH-2,H-6), 2.06-1.94 (5H, m, 2H of pipH-3, H-5, 3H of PhOpipH-3, H-5), 1.85(1H, m, 1H of PhOpipH-3, H-5), 1.62 (2H, m, 2H of pipH-3, H-5); m/z: 617[M+H]⁺.

Compound 412:6-(4-(3-acetamidophenoxy)piperidine-1-carbonyl)-N-(1-(4-methoxybenzyl)piperidin-4-yl)nicotinamide.¹H nmr (CDCl₃) δ 8.89 (1H, d, J 2.0 Hz, pyH-6), 8.12 (1H, dd, J 8.0, 2.0Hz, pyH-4), 7.62 (1H, d, J 7.5 Hz, pyH-3), 7.35 (2H, m, NHAc,C₆H₄NHAcH-2), 7.22 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 7.19 (1H, t, J 8.0Hz, C₆H₄NHAcH-5), 6.89 (1H, m, C₆H₄NHAcH-4 or H-6), 6.85 (2H, d, J 9.0Hz, 2H of C₆H₄OCH₃), 6.66 (1H, dd, J 8.0, 1.5 Hz, C₆H₄NHAcH-4 or H-6),6.29 (1H, d, J 8.0 Hz, NH), 4.60 (1H, m, PhOpipH-4), 4.01 (1H, m,pipH-4), 3.89 (2H, m, 2H of PhOpipH-2, H-6), 3.80 (3H, s, OCH₃), 3.69(1H, m, 1H of PhOpipH-2, H-6), 3.48 (2H, s, CH ₂C₆H₄OCH₃), 3.41 (1H, m,1H of PhOpipH-2, H-6), 2.86 (2H, m, 2H of pipH-2, H-6), 2.15 (5H, m,NHCOCH ₃, 2H of pipH-2, H-6), 2.03-1.92 (5H, m, 2H of pipH-3, H-5, 3H ofPhOpipH-3, H-5), 1.84 (1H, m, 1H of PhOpipH-3, H-5), 1.59 (2H, m, 2H ofpipH-3, H-5); m/z: 587 [M+H]⁺.

Compound 413:6-(4-(3-acetamidophenoxy)piperidine-1-carbonyl)-N-(1-(4-fluorobenzyl)piperidin-4-yl)nicotinamide.¹H nmr (CDCl₃) δ 8.89 (1H, m, pyH-6), 8.10 (1H, dd, J 8.0, 2.0 Hz,pyH-4), 7.56 (1H, d, J 8.0 Hz, pyH-3), 7.54 (1H, br s, C₆H₄NHAcH-2),7.36 (1H, s, NHAc), 7.29-7.25 (2H, m, 2H of C₆H₄F), 7.18 (1H, t, J 8.5Hz, C₆H₄NHAcH-5), 6.99 (2H, t, J 8.5 Hz, 2H of C₆H₄F), 6.90 (1H, d, J8.5 Hz, C₆H₄NHAcH-4 or H-6), 6.65 (1H, dd, J 8.5, 2.0 Hz, C₆H₄NHAcH-4 orH-6), 6.58 (1H, d, J 7.5 Hz, NH), 4.59 (1H, m, PhOpipH-4), 4.00 (1H, m,pipH-4), 3.87 (2H, m, 2H of PhOpipH-2, H-6), 3.66 (1H, m, 1H ofPhOpipH-2, H-6), 3.47 (1H, s, CH ₂C₆H₄F), 3.43 (1H, m, 1H of PhOpipH-2,H-6), 2.85 (2H, m, 2H of pipH-2, H-6), 2.14 (5H, m, NHCOCH ₃, 2H ofpipH-2, H-6), 2.02-1.90 (5H, m, 2H of pipH-3, H-5, 3H of PhOpipH-3,H-5), 1.83 (1H, m, 1H of PhOpipH-3, H-5), 1.61 (2H, m, 2H of pipH-3,H-5); ¹⁹F nmr (CDCl₃) δ −115.8; m/z: 574 [M+H]⁺.

Compound 414:6-(4-(3-acetamidophenoxy)piperidine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3-yl)nicotinamide.¹H nmr (CDCl₃) δ 9.85 (1H, s, NH), 8.93 (1H, d, J 1.5 Hz, pyH-6), 8.45(1H, d, J 2.5 Hz, N,O-pyH-6), 8.30 (1H, dd, J 8.5, 2.5 Hz, N,O-pyH-4),8.11 (1H, dd, J 8.5, 2.0 Hz, pyH-4) 7.66 (1H, s, NHAc), 7.39 (1H, d, J8.5 Hz, pyH-3), 7.34 (1H, br s, C₆H₄NHAcH-2), 7.17 (1H, t, J 8.0 Hz,C₆H₄NHAcH-5), 7.09-7.06 (4H, m, C₆H₄F), 6.90 (2H, m, C₆H₄NHAcH-4 or H-6,N,O-pyH-3), 6.64 (1H, d, J 8.0 Hz, C₆H₄NHAcH-4 or H-6), 4.56 (1H, m,PhOpipH-4), 3.93-3.77 (2H, m, 2H of PhOpipH-2, H-6), 3.59 (1H, m, 1H ofPhOpipH-2, H-6), 3.33 (1H, m, 1H of PhOpipH-2, H-6), 2.13 (3H, s, NHCOCH₃), 1.95-1.89 (3H, m, 3H of PhOpipH-3, H-5), 1.82 (1H, m, 1H ofPhOpipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −118.5; m/z: 570 [M+H]⁺.

Compound 415:N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(4-(trifluoromethylsulfonyl)phenoxy)piperidine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 8.87 (1H, s, pyH-4 or pyH-6), 8.08 (1H, s, pyH-4 orpyH-6), 7.93 (2H, d, 9.0 Hz, 2H of C₆ H ₄OCH₃), 7.60 (2H, d, J 8.5 Hz,2H of C₆H₄CN), 7.45 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 6.95 (2H, d, J 9.0Hz, 2H of C₆ H ₄OCH₃), 6.64 (1H, m, 1×NH), 4.94 (1H, m, 1×NH), 7.72 (1H,m, 1H of BzpipH-2, H-6), 4.05 (1H, m, pipH-4), 3.88 (3H, s, OCH₃), 3.56(2H, s, CH ₂C₆H₄CN), 3.56-3.41 (3H, m, BzpipH-4, 1H of BzpipH-2, H-6),3.13 (4H, m, 2H of BzpipH-2, H-6, CH₂CH₂CH ₂NHCO), 2.83 (2H, m, 2H ofpipH-2, H-6), 2.71 (2H, dd, J 7.0, 6.5 Hz, CH ₂CH₂CH₂NHCO), 2.20 (2H,dd, J 12.0, 9.5 Hz, 2H of pipH-2, H-6), 2.02 (4H, m, 2H of pipH-3, H-5,2H of BzpipH-3, H-5), 1.89 (2H, m, CH₂CH ₂CH₂NHCO), 1.76 (2H, m, 2H ofBzpipH-3, H-5), 1.67 (2H, m, 2H of pipH-3, H-5), 1.46 (9H, s, C(CH₃)₃);¹⁹F nmr (CDCl₃) δ −78.7; m/z: 656 [M+H]⁺.

Compound 416: tert-butyl3-(5-(1-(4-cyanobenzyl)piperidin-4-ylcarbamoyl)-2-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)pyridin-3-yl)propylcarbamate.¹H nmr (CDCl₃) δ 8.87 (1H, s, pyH-4 or H-6), 8.08 (1H, s, pyH-4 or H-6),7.93 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 7.60 (2H, d, J 8.5 Hz, 2H ofC₆H₄CN), 7.46 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 6.95 (2H, d, J 9.0 Hz, 2Hof C₆H₄OCH₃), 6.64 (1H, m, NH), 4.94 (1H, m, NHCOOC(CH₃)₃), 4.71 (1H, m,1H of BzpipH-2, H-6), 4.04 (1H, m, pipH-4), 3.88 (3H, s, OCH₃), 3.56(2H, s, CH ₂C₆H₄CN), 3.52-3.41 (2H, m, BzpipH-4, 1H of BzpipH-2, H-6),3.17-3.08 (4H, m, 2H of BzpipH-2, H-6, CH₂CH₂CH ₂NHCO), 2.83 (2H, m, 2Hof pipH-2, H-6), 2.71 (2H, dd, J 7.0, 6.5 Hz, CH₂CH ₂CH₂NHCO), 2.20 (2H,dd, J 12.0, 9.5 Hz, 2H of pipH-2, H-6), 2.02 (3H, m, 2H of pipH-3, H-5,1H of BzpipH-3, H-5), 1.94-1.82 (3H, m, 1H of BzpipH-3, H-5, CH₂CH₂CH₂NHCO), 1.76 (2H, m, 2H of BzpipH-3, H-5), 1.67 (2H, m, 2H of pipH-3,H-5), 1.46 (9H, s, C(CH₃)₃); m/z: 724 [M+H]⁺, 624 [M+H—CO₂—C₆H₄]⁺.

Compound 417:N-(1-(4-cyanophenyl)piperidin-4-yl)-6-(4-(4-fluorobenzyl)piperazine-1-carbonyl)nicotinamide.¹H nmr (CDCl₃) δ 8.86 (1H, d, J 2.0 Hz, pyH-6), 8.05 (1H, dd, J 8.5, 2.0Hz, pyH-4), 7.49 (1H, d, J 8.0 Hz, pyH-3), 7.57 (2H, d, J 9.0 Hz, 2H ofC₆H₄CN), 7.29-7.24 (2H, m, 2H of C₆H₄F), 7.00 (2H, t, J 8.5 Hz, 2H ofC₆H₄F), 6.87 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 6.85 (1H, m, NH), 4.23(1H, m, pipH-4), 3.99 (2H, m, 2H of pipH-2, H-6), 3.75, 3.73 (2H, 2 d,AB system, J 5.0 Hz, 2H of piz), 3.48 (2H, s, CH ₂C₆H₄F), 3.46 (2H, m,2H of piz), 3.07 (2H, t, J 12.0 Hz, 2H of pipH-2, H-6), 2.49, 2.48 (2H,2 d AB system, J 5.0 Hz, 2H of piz), 2.38, 2.37 (2H, 2 d AB system, J5.0 Hz, 2H of piz), 2.13 (2H, m, 2H of pipH-3, H-5), 1.66 (2H, m, 2H ofpipH-3, H-5); ¹⁹F nmr (CDCl₃) δ−115.4; m/z: 527 [M+H]⁺.

Compound 418:6-(4-(4-cyanophenoxy)piperidine-1-carbonyl)-N-(1-(4-cyanophenyl)piperidin-4-yl)nicotinamide.¹H nmr (CDCl₃) δ 8.90 (1H, m, pyH-6), 8.09 (1H, dd, J 8.0, 2.0 Hz,pyH-4), 7.59 (2H, d, J 9.0 Hz, 2H of 1×C₆H₄CN), 7.54 (1H, d, J 8.0 Hz,pyH-3), 7.47 (2H, d, J 9.0 Hz, 2H of 1×C₆H₄CN), 6.95 (2H, d, J 9.0 Hz,2H of 1×C₆H₄CN), 6.88 (2H, d, J 9.0 Hz, 2H of 1×C₆H₄CN), 6.79 (1H, d, J7.5 Hz, NH), 4.68 (1H, m, PhOpipH-4), 4.25 (1H, m, pipH-4), 3.92-3.81(4H, m, 2H of pipH-2, H-6, 2H of PhOpipH-2, H-6), 3.67 (1H, m, 1H ofPhOpipH-2, H-6), 3.46 (1H, m, 1H of PhOpipH-2, H-6), 3.07 (2H, t, J 12.0Hz, 2H of pipH-2, H-6), 2.14 (2H, m, 2H of pipH-3, H-5), 2.03-1.94 (3H,m, 3H of PhOpipH-3, H-5), 1.85 (1H, m, 1H of PhOpipH-3, H-5), 1.67 (2H,m, 2H of pipH-3, H-5); m/z: 535 [M+H]⁺.

Compound 419:N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(4-(thiophene-2-carbonyl)piperidine-1-carbonyl)picolinamide.¹H nmr (CDCl₃) δ 8.60 (1H, m, pyH-6), 8.24 (1H, d, J 8.0 Hz, pyH-3),7.93 (1H, d, J 8.5 Hz, NH), 7.88 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.75(1H, dd, J 3.5, 1.0 Hz, thiopheneH-3 or H-5), 7.68 (1H, dd, J 5.0, 1.0Hz, thiopheneH-3 or H-5), 7.61 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.45(2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.16 (1H, dd, J 5.0, 3.5 Hz,thiopheneH-4), 4.68 (1H, m, 1H of BzpipH-2, H-6), 4.01 (1H, m, pipH-4),3.78 (1H, m, 1H of BzpipH-2, H-6), 3.56 (2H, s, CH ₂C₆H₄CN), 3.41 (1H,m, BzpipH-4), 3.18 (2H, m, 2H of BzpipH-2, H-6), 2.81 (2H, m, 2H ofpipH-2, H-6), 2.23 (2H, dd, J 11.0, 9.5 Hz, 2H of pipH-2, H-6), 2.01(3H, m, 2H of pipH-3, H-5, 1H of BzpipH-3, H-5), 1.87 (3H, m, 3H ofBzpipH-3, H-5), 1.65 (2H, m, 2H of pipH-3, H-5); m/z: 542 [M+H]⁺.

Compound 420:6-(4-(4-cyanophenoxy)piperidine-1-carbonyl)-N-(1-(4-(methylsulfonyl)phenyl)piperidin-4-yl)nicotinamide.¹H nmr (CDCl₃) δ 8.90 (1H, d, J 2.0 Hz, pyH-6), 8.07 (1H, dd, J 8.0, 2.0Hz, pyH-4), 7.73 (2H, d, J 9.0 Hz, 2H of C₆H₄CN or C₆ H ₄SO₂CH₃), 7.57(2H, d, J 9.0 Hz, 2H of C₆H₄CN or C₆ H ₄SO₂CH₃), 7.46 (1H, d, J 8.0 Hz,pyH-3), 7.09 (1H, d, J 8.0 Hz, NH), 6.95 (2H, d, J 8.5 Hz, 2H of C₆H₄CNor C₆ H ₄SO₂CH₃), 6.93 (2H, d, J 9.0 Hz, 2H of C₆ H ₄CN or C₆H₄SO₂CH₃),4.67 (1H, m, PhOpipH-4), 4.26 (1H, m, pipH-4), 3.93 (2H, m, 2H ofpipH-2, H-6), 3.78 (2H, m, 2H of PhOpipH-2, H-6), 3.64 (1H, m, 1H ofPhOpipH-2, H-6), 3.45-3.37 (1H, m, 1H of PhOpipH-2, H-6), 3.09 (2H, t, J12.0 Hz, 2H of pipH-2, H-6), 3.00 (3H, s, SO₂CH₃), 2.10 (2H, m, 2H ofpipH-3, H-5), 1.98-1.90 (3H, m, 3H of PhOpipH-3, H-5), 1.84 (1H, m, 1Hof PhOpipH-3, H-5), 1.67 (2H, m, 2H of pipH-3, H-5); m/z: 588 [M+H]⁺.

Compound 421:6-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-N-(1-(4-(methylsulfonyl)phenyl)piperidin-4-yl)nicotinamide.¹H nmr (CDCl₃) δ 8.88 (1H, d, J 2.0 Hz, pyH-6), 8.06 (1H, dd, J 8.5, 2.0Hz, pyH-4), 7.73 (2H, d, J 9.0 Hz, 2H of C₆ H ₄SO₂CH₃), 7.46 (1H, d, J8.0 Hz, pyH-3), 7.25 (2H, m, 2H of C₆H₄F), 6.99 (3H, m, NH, 2H ofC₆H₄F), 6.93 (2H, d, J 9.0 Hz, 2H of C₆ H ₄SO₂CH₃), 4.24 (1H, m,pipH-4), 3.91 (2H, m, 2H of pipH-2, H-6), 3.74, 3.73 (2H, 2 d AB system,J 5.0 Hz, 2H of piz), 3.48 (2H, s, CH ₂C₆H₄F), 3.46 (2H, m, 2H of piz),3.08 (2H, t, J 11.5 Hz, 2H of pipH-2, H-6), 3.00 (3H, s, SO₂CH₃), 2.50,2.48 (2H, 2 d AB system, J 5.0 Hz, 2H of piz), 2.38, 2.36 (2H, 2 d ABsystem, J 5.0 Hz, 2H of piz), 2.11 (2H, m, 2H of pipH-3, H-5), 1.68 (2H,m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ−115.4; m/z: 581 [M+H]⁺.

Compound 422:6-(4-(4-cyanophenoxy)piperidine-1-carbonyl)-N-(1-(4-fluorophenyl)piperidin-4-yl)nicotinamide.¹H nmr (CDCl₃) δ 8.63 (1H, m, pyH-6), 7.85 (1H, dd, J 8.0, 2.0 Hz,pyH-4), 7.69 (1H, d, J 8.0 Hz, pyH-3), 7.59 (2H, d, J 9.0 Hz, 2H ofC₆H₄CN), 6.96 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 6.89 (2H, t, J 8.5 Hz, 2Hof C₆H₄F), 6.55 (2H, m, 2H of C₆H₄F), 4.70 (1H, m, PhOpipH-4), 4.58 (1H,m, pipH-4), 3.91 (2H, m, 2H of pipH-2, H-6 or PhOpipH-2, H-6), 3.78-3.71(2H, m, 2H of pipH-2, H-6 or PhOpipH-2, H-6), 3.57-3.47 (2H, m, 2H ofpipH-2, H-6 or PhOpipH-2, H-6), 3.17 (2H, m, 2H of pipH-2, H-6 orPhOpipH-2, H-6), 2.21-1.94 (7H, 7H of pipH-3, H-5, PhOpipH-3, H-5), 1.88(1H, m, 1H of pipH-3, H-5, PhOpipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −127.1;m/z: 528 [M+H]⁺.

Compound 423:6-(4-(4-cyanophenoxy)piperidine-1-carbonyl)-N-(1-(4-methoxyphenyl)piperidin-4-yl)nicotinamide.¹H nmr (CDCl₃) δ 8.92 (1H, m, pyH-6), 8.14 (1H, dd, J 8.0, 2.0 Hz,pyH-4), 7.63 (1H, d, J 8.5 Hz, pyH-3), 7.59 (2H, d, J 9.0 Hz, 2H ofC₆H₄CN), 6.95 (2H, d, J 9.0 Hz, 2H of C₆ H ₄CN), 6.92 (2H, d, J 9.0 Hz,2H of C₆H₄OCH₃), 6.84 (2H, d, J 9.5 Hz, 2H of C₆ H ₄OCH₃), 6.45 (1H, d,J 8.0 Hz, NH), 4.69 (1H, m, PhOpipH-4), 4.12 (1H, m, pipH-4), 3.93-3.84(2H, m, 2H of pipH-2, H-6, PhOpipH-2, H-6), 3.77 (3H, s, OCH3), 3.71(1H, m, 1H of pipH-2, H-6, PhOpipH-2, H-6), 3.53-3.49 (3H, m, 3H ofpipH-2, H-6, PhOpipH-3, H-6), 2.85 (2H, t, J 11.5 z, 2H of pipH2, H-6),2.15 (2H, m, 2H of pipH-3, H-5), 2.06-1.98 (3H, m, 3H of PhOpipH-3,H-5), 1.87 (1H, m, 1H of PhOpipH-3, H-5), 1.74 (2H, m, 2H of pipH-3,H-5); m/z: 540 [M+H]⁺.

Compound 424:6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)-N-(1-(3-(trifluoromethoxy)benzyl)piperidin-4-yl)nicotinamide.¹H nmr (CDCl₃) δ 8.91 (1H, m, pyH-6), 8.14 (1H, dd, J 8.0, 2.0 Hz,pyH-4), 7.94 (2H, d, J 8.5 Hz, 2H of C₆H₄OCH₃), 7.65 (1H, d, J 8.0 Hz,pyH-3), 7.33 (1H, t, J 8.0 Hz, C₆H₄OCF₃H-5), 7.24 (2H, m, C₆H₄OCF₃H-2and H-4 or H-6), 7.10 (1H, d, J 8.5 Hz, C₆H₄OCF₃H-4 or H-6), 6.95 (2H,d, J 9.0 Hz, 2H of C₆H₄OCH₃), 6.22 (1H, d, J 8.0 Hz, NH), 4.69 (1H, m,1H of BzpipH-2, H-6), 4.03 (1H, m, pipH-4), 3.94 (1H, m, 1H of BzpipH-2,H-6), 3.88 (3H, s, OCH3), 3.54 (3H, m, CH ₂C₆H₄OCF₃, BzpipH-4), 3.26(1H, m, 1H of BzpipH-2, H-6), 3.11 (1H, m, 1H of BzpipH-2, H-6), 2.85(2H, m, 2H of pipH-2, H-6), 2.21 (2H, dd, J 11.0, 9.5 Hz, 2H of pipH-2,H-6), 2.04 (3H, m, 2H of pipH-3, H-5, 1H of BzpipH-3, H-5), 1.93-1.81(3H, m, 3H of BzpipH-3, H-5), 1.63 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr(CDCl₃) δ −57.7; m/z: 625 [M+H]⁺.

Compound 425:6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)-N-(1-(3-methoxybenzyl)piperidin-4-yl)nicotinamide.¹H nmr (CDCl₃) δ 8.90 (1H, m, pyH-6), 8.12 (1H, dd, J 8.5, 2.0 Hz,pyH-4), 7.93 (2H, d, J 8.5 Hz, 2H of COC₆H₄OCH₃), 7.57 (1H, d, J 7.5 Hz,pyH-3), 7.22 (1H, t, J 8.0 Hz, C₆H₄OCH₃H-5), 6.95 (2H, d, J 9.0 Hz, 2Hof COC₆H₄OCH₃), 6.89 (2H, m, C₆H₄OCH₃H-2 and H-4 or H-6), 6.80 (1H, dd,J 8.5, 2.0 Hz, C₆H₄OCH₃H-4 or H-6), 6.59 (1H, d, J 8.0 Hz, NH), 4.68(1H, m, 1H of BzpipH-2, H-6), 4.01 (1H, m, pipH-4), 3.89 (1H, m, 1H ofBzpipH-2, H-6), 3.87 (3H, s, 1×OCH₃), 3.80 (3H, s, 1×OCH₃), 3.53 (2H, s,CH ₂C₆H₄OCH₃), 3.51 (1H, m, BzpipH-4), 3.24 (1H, ddd, J 14.0, 10.0, 4.0Hz, 1H of BzpipH-2, H-6), 3.10 (1H, m, 1H of BzpipH-2, H-6), 2.91 (2H,m, 2H of pipH-2, H-6), 2.22 (2H, dd, J 11.5, 10.0 Hz, 2H of pipH-2,H-6), 2.04-2.00 (3H, m, 2H of pipH-3, H-5, 1H of BzpipH-3, H-5),1.91-1.79 (3H, m, 3H of BzpipH-3, H-5), 1.65 (2H, m, 2H of pipH-3, H-5);m/z: 571 [M+H]⁺.

426:N-((3S,4R)-3-fluoro-1-((5-methylisoxazol-3-yl)methyl)piperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide.¹H nmr (CDCl₃) δ 8.89 (1H, d, J 2.0 Hz, pyH-6), 8.10 (1H, dd, J 8.0, 2.0Hz, pyH-4), 7.94 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 7.53 (1H, d, J 8.0Hz, pyH-3), 7.09 (1H, d, J 7.5 Hz, NH), 6.95 (2H, d, J 9.0 Hz, 2H ofC₆H₄OCH₃), 5.97 (1H, d, J 1.0 Hz, isoxazoleH-4), 4.70-4.62 (1.5H, m, 1Hof BzpipH-2, H-6, 0.5H of pipH-3), 4.49 (0.5H, dt, J 5.0, 9.5 Hz, 0.5Hof pipH-3), 4.12 (1H, m, pipH-4), 3.87 (3H, s, OCH₃), 3.84 (1H, m, 1H ofBzpipH-2, H-6), 3.64 (2H, s, CH ₂isoxazole), 3.53 (1H, m, BzpipH-4),3.26-20 (2H, m, 1H of pipH-6, 1H of BzpipH-2, H-6), 3.11 (1H, t, J 11.0Hz, 1H of BzpipH-2, H-6), 2.84 (m, 1H of pipH-2), 2.41 (3H, d, J 1.0 Hz,isoxazoleCH3), 2.32 (1H, m, 1H of pipH-6), 2.27-2.18 (2H, m, 1H ofpipH-2, 1H of pipH-5), 2.02 (1H, m, BzpipH-3, H-5), 1.92-1.80 (3H, m, 3Hof BzpipH-3, H-5) 1.63 (1H, m, 1H of pipH-5); ¹⁹F nmr (CDCl₃) δ −188.6;m/z: 565 [M+H]⁺.

Compound 427:N-((3S,4R)-3-fluoro-1-((2-methylthiazol-4-yl)methyl)piperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide.¹H nmr (CDCl₃) δ 8.94 (1H, m, pyH-6), 8.16 (1H, dd, J 8.5, 2.0 Hz,pyH-4), 7.93 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 7.59 (1H, d, J 8.0 Hz,pyH-3), 6.96 (2H, J 9.0 Hz, 2H of C₆H₄OCH₃), 6.95 (1H, s, thiazoleH-4),4.68 (1H, m, 1H of BzpipH-2, H-6), 4.55 (1H, ddt, J 50.0, 5.0, 9.5 Hz,pipH-3), 4.15 (1H, m, pipH-4), 3.92 (1H, m, 1H of BzpipH-2, H-6), 3.87(3H, s, OCH₃), 3.71, 3.64 (2H, 2 d AB system, J 13.0 Hz, CH₂thiazole),3.51 (1H, m, BzpipH-4), 3.29-3.20 (2H, m, 1H of pipH-6, 1H of BzpipH-2,H-6), 3.10 (1H, dd, J 12.5, 11.0 Hz, 1H BzpipH-2, H-6), 2.89 (1H, m, 1Hof pipH-2), 2.71 (3H, s, thiazoleCH₃), 2.27-2.12 (3H, m, 1H of pipH-2,1H of pipH-5, 1H of pipH-6), 2.02 (1H, m, 1H of BzpipH-3, H-5),1.91-1.80 (3H, m, 3H of BzpipH-3, H-5), 1.61 (1H, m, 1H of pipH-5); ¹⁹Fnmr (CDCl₃) δ −188.6; m/z: 581 [M+H]⁺.

Compound 428:6-(4-(4-acetamidophenoxy)piperidine-1-carbonyl)-N-(1-(3-(trifluoromethoxy)benzyl)piperidin-4-yl)nicotinamide.¹H nmr (CDCl₃) δ 8.90 (1H, m, pyH-6), 8.11 (1H, dd, J 8.5, 2.0 Hz,pyH-4), 7.58 (1H, d, J 8.5 Hz, pyH-3), 7.38 (2H, d, J 9.0 Hz, 2H ofC₆H₄NHAc), 7.32 (1H, t, J 8.0 Hz, C₆H₄OCF₃H-5), 7.31 (1H, m, 1×NH), 7.23(2H, m, C₆H₄OCF₃H-2, H-4 or H-6), 7.09 (1H, d, J 8.0 Hz, C₆H₄OCF₃H-4 orH-6), 6.86 (2H, d, J 9.0 Hz, 2H of C₆H₄NHAc), 6.49 (1H, m, 1×NH), 4.54(1H, m, PhOpipH-4), 4.01 (1H, m, pipH-4), 3.88 (2H, m, 2H of PhOpipH-2,H-6), 3.68 (1H, m, 1H of PhOpipH-2, H-6), 3.52 (2H, s, CH ₂C₆H₄OCF₃),3.47-3.40 (1H, m, 1H of PhOpipH-2, H-6), 2.85 (2H, m, 2H of pipH-2,H-6), 2.18 (2H, t, J 11.5 Hz, 2H of pipH-2, H-6), 2.14 (3H, s, NHCOCH₃), 2.04-1.90 (5H, m, 2H of pipH-3, H-5, 3H of PhOpipH-3, H-5), 1.80(1H, m, 1H of PhOpipH-3, H-5), 1.62 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr(CDCl₃) δ −57.7; m/z: 640 [M+H]⁺.

Compound 429:6-(4-(3-acetamidophenoxy)piperidine-1-carbonyl)-N-(1-(3-(trifluoromethoxy)benzyl)piperidin-4-yl)nicotinamide.¹H nmr (CDCl₃) δ 8.89 (1H, m, pyH-6), 8.12 (1H, dd, J 8.0, 2.0 Hz,pyH-4), 7.59 (1H, d, J 8.0 Hz, pyH-3), 7.48 (1H, s, 1×NH), 7.36 (1H, s,C₆H₄NHAcH-2), 7.32 (1H, m, C₆H₄NHAcH-5), 7.24-7.16 (3H, m, C₆H₄OCF₃H-2,H-4 or H-6, C₆H₄NHAcH-5), 7.10 (1H, d, J 8.5 Hz, C₆H₄OCF₃H-4 or H-6),6.90 (1H, d, J 8.0 Hz, C₆H₄NHAcH-4 or H-6), 6.65 (1H, d, J 8.0 Hz,C₆H₄NHAcH-4 or H-6), 6.50 (1H, d, J 8.0 Hz, NH), 4.59 (1H, m,PhOpipH-4), 4.01 (1H, m, pipH-4), 3.88 (2H, m, 2H of PhOpipH-2, H-6),3.67 (1H, m, 1H of PhOpipH-2, H-6), 3.52 (2H, s, CH ₂C₆H₄OCF₃), 3.44(1H, m, 1H of PhOpipH-2, H-6), 2.85 (2H, m, 2H of pipH-2, H-6), 2.18(2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 2.15 (3H, s, NHCOCH ₃), 2.08-1.91(5H, m, 2H of pipH-3, H-5, 3H of PhOpipH-3, H-5), 1.81 (1H, m, 1H ofPhOpipH-3, H-5), 1.62 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ−57.7; m/z: 641 [M+H]⁺.

Compound 430:6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)-N-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)nicotinamide.¹H nmr (CDCl₃) δ 8.81 (1H, m, pyH-6), 8.14 (1H, dd, J 8.0, 2.0 Hz,pyH-4), 7.94 (2H, d, J 8.5 Hz, 2H of C₆ H ₄OCH₃), 7.63 (1H, d, J 8.0 Hz,pyH-3), 7.34 (2H, d, J 9.0 Hz, 2H of C₆H₄OCF₃), 7.15 (2H, d, J 8.0 Hz,2H of C₆H₄OCF₃), 6.96 (2H, d, J 9.5 Hz, 2H of C₆ H ₄OCH₃), 6.26 (1H, d,J 8.0 Hz, NH), 4.69 (1H, m, 1H of BzpipH-2, H-6), 4.02 (1H, m, pipH-4),3.94 (1H, m, 1H of BzpipH-2, H-6), 3.88 (3H, s, OCH₃), 3.53 (1H, m,BzpipH-4), 3.51 (2H, s, CH ₂C₆H₄OCF₃), 3.25 (1H, ddd, J 14.0, 10.0, 4.0Hz, 1H of BzpipH-2, H-6), 3.11 (1H, m, 1H of BzpipH-2, H-6), 2.85 (2H,m, 2H of pipH-2, H-6), 2.18 (2H, dd, J 11.5, 9.5 Hz, 2H of pipH-2, H-6),2.02 (2H, m, 2H of pipH-3, H-5), 1.93-1.73 (4H, m, BzpipH-3, H-5), 1.61(2H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −57.9; m/z: 626 [M+H]⁺.

Compound 431:N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(3-(cyclopropanecarboxamido)phenoxy)piperidine-1-carbonyl)nicotinamide.¹H nmr (CDCl₃) δ 8.83 (1H, m, pyH-6), 8.05 (1H, dd, J 8.0, 2.0 Hz,pyH-4), 7.56-7.52 (3H, m, 2H of C₆H₄CN, pyH-3), 7.39-3.37 (4H, m, 2H ofC₆H₄CN, 1×NH, C₆H₄NH-2), 7.13 (1H, t, J 8.0 Hz, C₆H₄NH-5), 6.79 (1H, dd,J 8.0, 1.5 Hz, C₆H₄NH-4 or H-6), 6.58 (1H, dd, J 8.0, 2.0 Hz, C₆H₄NH-4or H-6), 6.26 (1H, d, J 7.5 Hz, 1×NH), 4.55 (1H, m, PhOpipH-4), 3.96(1H, m, pipH-4), 3.82 (2H, m, 2H of PhOpipH-2, H-6), 3.61 (1H, m, 1H ofPhOpipH-2, H-6), 3.49 (2H, s, CH ₂C₆H₄CN), 3.42-3.35 (1H, m, 1H ofPhOpipH-2, H-6), 2.76 (2H, m, 2H of pipH-2, H-6), 2.14 (2H, dd, J 11.5,9.5 Hz, 2H of pipH-2, H-6), 1.99-1.82 (5H, m, 2H of pipH-3, H-5, 3H ofPhOpipH-3, H-5), 1.78 (1H, m, 1H of PhOpipH-3, H-5), 1.54 (2H, m, 2H ofpipH-3, H-5), 1.43 (1H, m cPrH-1), 1.01 (2H, m, 2H of cPrH-2, H-3), 0.79(2H, m, 2H of cPrH-2, H-3); m/z: 608 [M+H]⁺.

Compound 432:6-(4-(3-(cyclopropanecarboxamido)phenoxy)piperidine-1-carbonyl)-N-(1-(4-fluorobenzyl)piperidin-4-yl)nicotinamide.¹H nmr (CDCl₃) δ 8.81 (1H, m, pyH-6), 8.03 (1H, dd, J 8.0, 2.0 Hz,pyH-4), 7.63 (1H, s, 1×NH), 7.50 (1H, d, J 8.5 Hz, pyH-3), 7.36 (1H, s,C₆H₄NH-2), 7.23-7.18 (2H, m, 2H of C₆H₄F), 7.11 (1H, t, J 8.0 Hz,C₆H₄NH-5), 6.92 (2H, t, J 9.0 Hz, 2H of C₆H₄F), 6.82 (1H, dd, J 8.0, 1.0Hz, C₆H₄NH-4 or H-6), 6.57 (1H, dd, J 8.0, 1.5 Hz, C₆H₄NH-4 or H-6),6.45 (1H, d, J 8.0 Hz, 1×NH), 4.52 (1H, m, PhOpipH-4), 3.94 (1H, m,pipH-4), 3.80 (2H, m, 2H of PhOpipH-2, H-6), 3.58 (1H, m, 1H ofPhOpipH-2, H-6), 3.41 (2H, s, CH ₂C₆H₄F), 3.34 (1H, m, 1H of PhOpipH-2,H-6), 2.77 (2H, m, 2H of pipH-2, H-6), 2.08 (2H, dd, J 11.5, 9.5 Hz, 2Hof pipH-2, H-6), 1.95-1.80 (5H, 2H of pipH-3, H-5, 3H of PhOpipH-3,H-5), 1.75 (1H, m, 1H of PhOpipH-3, H-5), 1.53 (2H, m, 2H of pipH-3,H-5), 1.45 (1H, m, cPrH-1), 0.99 (2H, m, 2H of cPrH-2, H-3), 0.77 (2H,m, 2H of cPrH-2, H-3); ¹⁹F nmr (CDCl₃) δ −115.9; m/z: 601 [M+H]⁺.

Compound 433:6-(4-(3-(cyclopropanecarboxamido)phenoxy)piperidine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3-yl)nicotinamide.¹H nmr (CDCl₃) δ 9.56 (1H, s, 1×NH), 8.85 (1H, m, pyH-6), 8.38 (1H, d, J2.5 Hz, N,O-pyH-6), 8.24 (1H, dd, J 9.0, 2.5 Hz, N,O-pyH-4), 8.04 (1H,dd, J 8.5, 2.0 Hz, pyH-4), 7.56 (1H, s, 1×NH), 7.36 (1H, s, C₆H₄NH-2),7.34 (1H, d, J 8.5 Hz, pyH-3), 7.11 (1H, t, J 8.0 Hz, C₆H₄NH-5),7.03-6.99 (4H, m, C₆H₄F), 6.86 (1H, d, J 8.5 Hz, N,O-pyH-3), 6.78 (1H,dd, J 8.0, 1.5 Hz, C₆H₄NH-4 or H-6), 6.57 (1H, dd, J 8.0, 2.0 Hz,C₆H₄NH-4 or H-6), 4.52 (1H, m, PhOpipH-4), 3.87 (1H, m, 1H of PhOpipH-2,H-6), 3.74 (1H, m, 1H of PhOpipH-2, H-6), 3.52 (1H, m, 1H of PhOpipH-2,H-6), 3.27 (1H, m, 1H of PhOpipH-2, H-6), 1.91-1.76 (4H, m, PhOpipH-3,H-5), 1.43 (1H, m, cPrH-1), 0.99 (2H, m, 2H of cPrH-2, H-3), 0.789 (2H,m, 2H of cPrH-2, H-3); ¹⁹F nmr (CDCl₃) δ −118.5; m/z: 596 [M+H]⁺.

Compound 434:N-((cis)-4-(4-cyanophenoxy)cyclohexyl)-6-(4-(3-(cyclopropanecarboxamido)phenoxy)piperidine-1-carbonyl)nicotinamide.¹H nmr (CDCl₃) δ 8.85 (1H, m, pyH-6), 8.05 (1H, dd, J 8.0, 2.0 Hz,pyH-4), 7.61 (1H, s, 1×NH), 7.48 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 7.40(1H, s, C₆H₄NH-2), 7.11 (1H, t, J 8.0 Hz, C₆H₄NH-5), 6.87 (2H, d, J 9.0Hz, 2H of C₆H₄CN), 6.80 (1H, dd, J 8.0, 1.0 Hz, C₆H₄NH-4 or H-6), 6.64(1H, d, J 8.0 Hz, 1×NH), 6.57 (1H, dd, J 8.0, 2.0 Hz, C₆H₄NH-4 or H-6),4.54 (2H, m, cHexH-1, PhOpipH-4), 4.04 (1H, m, cHexH-4), 3.83 (1H, m, 1Hof PhOpipH-2, H-6), 3.77 (1H, m, 1H of PhOpipH-2, H-6), 3.58 (1H, m, 1Hof PhOpipH-2, H-6), 3.35 (1H, m, 1H of PhOpipH-2, H-6), 2.04 (2H, m, 2Hof cHexH-2, H-6), 1.94-1.80 (4H, m, 4H of cHexH-2, H-3, H-5, H-6,PhOpipH-3, H-5), 1.80-1.64 (6H, m, 6H of cHexH-2, H-3, H-5, H-6,PhOpipH-3, H-5), 1.45 (1H, m, cPrH-1), 0.99 (2H, m, 2H of cPrH-2, H-3),0.78 (2H, m, 2H of cPrH-2, H-3); m/z: 609 [M+H]⁺.

Compound 435:6-(4-(3-(cyclopropanecarboxamido)phenoxy)piperidine-1-carbonyl)-N-(1-(4-methoxybenzyl)piperidin-4-yl)nicotinamide.¹H nmr (CDCl₃) δ 8.82 (1H, m, pyH-6), 8.04 (1H, dd, J 8.5, 2.0 Hz,pyH-4), 7.54 (1H, s, 1×NH), 7.52 (1H, d, J 8.5 Hz, pyH-3), 7.36 (1H, s,C₆H₄NH-2), 7.15 (2H, d, J 8.5 Hz, 2H of C₆ H ₄OCH₃), 7.11 (1H, t, J 8.5Hz, C₆H₄NH-5), 6.82 (1H, m, C₆H₄NH-4 or H-6), 6.79 (2H, d, J 8.5 Hz, 2Hof C₆ H ₄OCH₃), 6.57 (1H, dd, J 8.0, 2.0 Hz, C₆H₄NH-4 or H-6), 6.31 (1H,d, J 7.5 Hz, 1×NH), 4.53 (1H, m, PhOpipH-4), 3.93 (1H, m, pipH-4), 3.81(2H, m, 2H of PhOpipH-2, H-6), 3.73 (3H, s, OCH₃), 3.59 (1H, m, 1H ofPhOpipH-2, H-6), 3.39 (2H, s, CH ₂C₆H₄OCH₃), 3.33 (1H, m, 1H ofPhOpipH-2, H-6), 2.79 (2H, m, 2H of pipH-2, H-6), 2.08 (2H, dd, J 11.5,9.5 Hz, 2H of pipH-2, H-6), 1.96-1.71 (6H, m, 2H of pipH-3, H-5,PhOpipH-3, H-5), 1.53 (2H, m, 2H of pipH-3, H-5), 1.47-1.39 (1H, m,cPrH-1), 1.00 (2H, m, 2H of cPrH-2, H-3), 0.77 (2H, m, 2H of cPrH-2,H-3); m/z: 613 [M+H]⁺.

Compound 436:N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(4-(trifluoromethylthio)phenoxy)piperidine-1-carbonyl)pyridazine-3-carboxamide.¹H nmr (CDCl₃) δ 8.42 (1H, d, J 9.0 Hz, pyH-5 or H-6), 8.07 (1H, d, J8.0 Hz, NH), 8.01 (1H, d, J 8.5 Hz, pyH-5 or H-6), 7.62 (2H, d, J 8.0Hz, 2H of C₆H₄CN), 7.58 (2H, d, J 8.5 Hz, 2H of C₆H₄SCF₃), 7.46 (2H, d,J 8.0 Hz, 2H of C₆H₄CN), 6.95 (2H, d, J 9.0 Hz, 2H of C₆H₄SCF₃), 4.71(1H, m, PhOpipH-4), 4.10-4.03 (2H, m, pipH-4, 1H of PhOpipH-2, H-6),3.88 (1H, m, 1H of PhOpipH-2, H-6), 3.82 (1H, ddd, J 13.0, 8.5, 4.5 Hz,1H of PhOpipH-2, H-6), 3.71-3.64 (1H, m, 1H of PhOpipH-2, H-6), 3.57(2H, s, CH ₂C₆H₄CN), 2.84 (2H, m, 2H of pipH-2, H-6), 2.24 (2H, dd, J11.0, 9.5 Hz, 2H of pipH-2, H-6), 2.15-1.97 (6H, m, 2H of pipH-3, H-5,PhOpipH-3, H-5), 1.67 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ−43.8; m/z: 625 [M+H]⁺.

Compound 437:6-(4-(4-acetylphenoxy)piperidine-1-carbonyl)-N-(1-(4-cyanobenzyl)piperidin-4-yl)pyridazine-3-carboxamide.¹H nmr (CDCl₃) δ 8.43 (1H, d, J 8.5 Hz, pyH-5 or H-6), 8.07 (1H, d, J8.0 Hz, NH), 8.01 (1H, d, J 9.0 Hz, pyH-5 or H-6), 7.94 (2H, d, J 9.0Hz, 2H of C₆H₄Ac), 7.62 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.46 (2H, d, J8.5 Hz, 2H of C₆H₄CN), 6.96 (2H, d, J 9.5 Hz, 2H of C₆H₄Ac), 4.78 (1H,m, PhOpipH-4), 4.11-4.04 (2H, m, pipH-4, 1H of PhOpipH-2, H-6), 3.89(1H, m, 1H of PhOpipH-2, H-6), 3.83 (1H, m, 1H of PhOpipH-2, H-6),3.72-3.65 (1H, m, 1H of PhOpipH-2, H-6), 3.57 (2H, s, CH ₂C₆H₄CN), 2.83(2H, m, 2H of pipH-2, H-6), 2.56 (3H, s, COCH₃), 2.23 (2H, dd, J 11.0,9.5 Hz, 2H of pipH-2, H-6), 2.16-2.02 (6H, m, 2H of pipH-3, H-5,PhOpipH-3, H-5), 1.67 (2H, m, 2H of pipH-3, H-5); m/z: 568 [M+H]⁺.

Compound 438:6-(4-(3-(cyclopropanecarboxamido)phenoxy)piperidine-1-carbonyl)-N-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)nicotinamide.¹H nmr (CDCl₃) δ 8.90 (1H, m, pyH-6), 8.13 (1H, dd, J 8.5, 2.0 Hz,pyH-4), 7.63 (1H, d, J 8.0 Hz, pyH-3), 7.46 (2H, m, C₆H₄NH-2, 1×NH),7.34 (2H, d, J 8.5 Hz, 2H of C₆H₄OCF₃), 7.19-7.14 (3H, m, 2H ofC₆H₄OCF₃, C₆H₄NH-5), 6.86 (1H, d, J 8.5 Hz, C₆H₄NH-4 or H-6), 6.65 (1H,dd, J 8.5, 2.0 Hz, C₆H₄NH-4 or H-6), 6.23 (1H, d, J 8.0 Hz, 1×NH), 4.61(1H, m, PhOpipH-4), 4.02 (1H, m, pipH-4), 3.95-3.84 (2H, m, 2H ofPhOpipH-2, H-6), 3.68 (1H, m, 1H of PhOpipH-2, H-6), 3.51 (2H, s, CH₂C₆H₄OCF₃), 3.44 (1H, m, 1H of PhOpipH-2, H-6), 2.85 (2H, m, 2H ofpipH-2, H-6), 2.18 (2H, t, J 11.5 Hz, 2H of pipH-2, H-6), 2.05-1.92 (5H,m, 2H of pipH-3, H-5, 3H of PhOpipH-3, H-5), 1.84 (1H, m, 1H ofPhOpipH-3, H-5), 1.59 (2H, m, 2H of pipH-3, H-5), 1.49 (1H, m, cPrH-1),1.08 (2H, m, 2H of cPrH-2, H-3), 0.85 (2H, m, 2H of cPrH-2, H-3); ¹⁹Fnmr (CDCl₃) δ −57.9; m/z: 666 [M+H]⁺ (found [M+H]⁺, 666.3879,C₃₅H₃₈F₃N₅O₅ requires [M+H]⁺ 666.2898).

Compound 439:N-(1-(4-methoxybenzyl)piperidin-4-yl)-6-(4-(4-(pyrrolidin-1-yl)benzoyl)piperidine-1-carbonyl)nicotinamide.¹H nmr (CDCl₃) δ 8.90 (1H, m, pyH-6), 8.12 (1H, dd, J 8.0, 2.0 Hz,pyH-4), 7.86 (2H, d, J 8.5 Hz, 2H of C₆H₄N), 7.61 (1H, d, J 8.5 Hz,pyH-3), 7.22 (2H, d, J 8.5 Hz, 2H of C₆ H ₄OCH₃), 6.85 (2H, d, J 9.0 Hz,2H of C₆ H ₄OCH₃), 6.52 (2H, d, J 9.0 Hz, 2H of C₆H₄N), 6.32 (1H, m,NH), 4.69 (1H, m, 1H of BzpipH-2, H-6), 4.01 (1H, m, pipH-4), 3.90 (1H,m, 1H of BzpipH-2, H-6), 3.79 (3H, s, OCH₃), 3.53 (1H, m, BzpipH-4),3.49 (2H, s, CH ₂C₆H₄OCH₃), 3.38, 3.35 (4H, 2 d AB system, J 6.5 Hz, 4Hof pyrrolidine), 3.24 (1H, m, 1H of BzpipH-2, H-6), 3.08 (1H, m, 1H ofBzpipH-2, H-6), 2.88 (2H, m, 2H of pipH-2, H-6), 2.19 (2H, t, J 11.0 Hz,2H of pipH-2, H-6), 2.05, 2.02 (4H, 2 d AB system, J 6.5 Hz, 4H ofpyrrolidine), 1.98 (2H, m, 2H of pipH-3, H-5), 1.91-1.78 (4H, m,BzpipH-3, H-5), 1.61 (2H, m, 2H of pipH-3, H-5); m/z: 611 [M+H]⁺.

Compound 440:6-(4-(4-(pyrrolidin-1-yl)benzoyl)piperidine-1-carbonyl)-N-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)nicotinamide.¹H nmr (CDCl₃) δ 8.92 (1H, m, pyH-6), 8.13 (1H, dd, J 8.0, 2.0 Hz,pyH-4), 7.87 (2H, d, J 9.0 Hz, 2H of C₆H₄N), 7.56 (1H, d, J 8.5 Hz,pyH-3), 7.34 (2H, d, J 8.5 Hz, 2H of C₆H₄OCF₃), 7.14 (2H, d, J 8.0 Hz,2H of C₆H₄OCF₃), 6.60 (1H, d, J 7.5 Hz, NH), 6.52 (2H, d, J 9.0 Hz, 2Hof C₆H₄N), 4.69 (1H, m, 1H of BzpipH-2, H-6), 4.01 (1H, m, pipH-4), 3.88(1H, m, 1H of BzpipH-2, H-6), 3.52 (1H, m, BzpipH-4), 3.50 (2H, s,CH2C6H4OCF3), 3.38, 3.35 (4H, 2 d AB system, J 6.5 Hz, 4H ofpyrrolidine), 3.23 (1H, m, 1H of BzpipH-2, H-6), 3.09 (1H, m, 1H ofBzpipH-2, H-6), 2.85 (2H, m, 2H of pipH-2, H-6), 2.18 (2H, mdd, J 11.5,10.0 Hz, 2H of pipH-2, H-6), 2.05, 2.03 (4H, 2 d AB system, J 6.5 Hz, 4Hof pyrrolidine), 1.98 (2H, m, 2H of pipH-3, H-5), 1.92-1.76 (4H, m,BzpipH-3, H-5), 1.63 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ−57.9; m/z: 665 [M+H]⁺.

Compound 441:6-(4-(4-(pyrrolidin-1-yl)benzoyl)piperidine-1-carbonyl)-N-(1-(3-(trifluoromethoxy)benzyl)piperidin-4-yl)nicotinamide.¹H nmr (CDCl₃) δ 8.84 (1H, m, pyH-6), 8.05 (1H, dd, J 8.5, 2.0 Hz,pyH-4), 7.80 (2H, d, J 9.0 Hz, 2H of C₆H₄N), 7.49 (1H, d, J 8.0 Hz,pyH-3), 7.25 (1H, t, J 7.5 Hz, C₆H₄OCF₃H-5), 7.17 (2H, m, C₆H₄OCF₃H-2,H-4 or H-6), 7.02 (1H, d, J 8.0 Hz, C₆H₄OCF₃H-4 or H-6), 6.54 (1H, d, J8.0 Hz, NH), 6.46 (2H, d, J 9.0 Hz, 2H of C₆H₄N), 4.64 (1H, m, 1H ofBzpipH-2, H-6), 3.95 (1H, m, pipH-4), 3.82 (1H, m, 1H of BzpipH-2, H-6),3.46 (2H, s, CH ₂C₆H₄OCF₃), 3.42 (1H, m, BzzpipH-4), 3.31, 3.29 (4H, 2 dAB system, J 6.5 Hz, 4H of pyrrolidine), 3.17 (1H, m, 1H of BzpipH-2,H-6), 3.02 (1H, m, 1H of BzpipH-2, H-6), 2.78 (2H, m, 2H of pipH-2,H-6), 2.12 (2H, dd, J 11.5, 9.5 Hz, 2H of pipH-2, H-6), 1.99-1.95 (6H,m, 4H of pyrrolidine, 2H of pipH-3, H-5), 1.86-1.72 (4H, m, BzpipH-3,H-5), 1.57 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −57.7; m/z: 665[M+H]⁺.

Compound 442:N-((cis)-4-(4-cyanophenoxy)cyclohexyl)-6-(4-(4-(pyrrolidin-1-yl)benzoyl)piperidine-1-carbonyl)nicotinamide.¹H nmr (CDCl₃) δ 8.82 (1H, m, pyH-6), 7.86 (2H, d, J 9.0 Hz, 2H ofC₆H₄N), 7.57-7.52 (3H, m, 2H of C₆H₄CN, pyH-3), 6.93 (2H, d, J 9.0 Hz,2H of C₆H₄CN), 6.77 (1H, d, J 8.0 Hz, NH), 6.53 (2H, d, J 9.0 Hz, 2H ofC₆H₄N), 4.69 (1H, m, 1H of BzpipH-2, H-6), 4.61 (1H, br s, cHexH-1),4.11 (1H, m, cHexH-4), 3.88 (1H, m, 1H of BzpipH-2, H-6), 3.48 (1H, mBzpipH-4), 3.38, 3.36 (4H, 2 d AB system, J 6.5 Hz, 4H of pyrrolidine),3.23 (1H, m, 1H of BzpipH-2, H-6), 3.08 (1H, m, 1H of BzpipH-2, H-6),2.12-2.09 (2H, m, 2H of cHexH-2, H-3, H-5, H-6), 2.05, 2.03 (4H, 2 d ABsystem, J 6.5 Hz, 4H of pyrrolidine), 1.98-1.90 (2H, m, 2H of cHexH-2,H-3, H-5, H-6, BzpipH-3, H-5), 1.88-1.69 (8H, 8H of cHexH-2, H-3, H-5,H-6, BzpipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −118.6; m/z: 607 [M+H]⁺(found[M+H]⁺, 606.3158, C₃₆H₃₉N₅O₄ requires [M+H]⁺ 606.3075).

Compound 443:N-(1-(3-fluoro-4-methoxybenzyl)piperidin-4-yl)-6-(4-(4-(pyrrolidin-1-yl)benzoyl)piperidine-1-carbonyl)nicotinamide.¹H nmr (CDCl₃) δ 8.91 (1H, m, pyH-6), 8.12 (1H, dd, J 8.5, 2.0 Hz,pyH-4), 7.87 (2H, d, J 9.0 Hz, 2H of C₆H₄N), 7.59 (1H, d, J 8.0 Hz,pyH-3), 7.08 (1H, dd, J 12.0, 2.0 Hz, C₆H₃FOCH₃H-2), 6.99 (1H, d, J 8.5Hz, C₆H₃FOCH₃H-6), 6.89 (1H, t, J 8.5 Hz, C₆H₃FOCH₃H-5), 6.53 (2H, d, J9.0 Hz, 2H of C₆H₄N), 6.49 (1H, d, J 8.5 Hz, NH), 4.70 (1H, m, 1H ofBzpipH-2, H-6), 4.01 (1H, m, pipH-4), 3.89 (1H, m, 1H of BzpipH-32,H-6), 3.87 (3H, s, OCH₃), 3.50 (1H, m, BzpipH-4), 3.43 (2H, s,CH₂C₆H₃FOCH₃), 3.38, 3.36 (4H, 2 d AB system, J 6.5 Hz, 4H ofpyrrolidine), 3.24 (1H, m, 1H of BzpipH-2, H-6), 3.09 (1H, m, 1H ofBzpipH-2, H-6), 2.84 (2H, m, 2H of pipH-2, H-6), 2.15 (2H, t, J 11.5 Hz,2H of pipH-2, H-6), 2.05, 2.03 (4H, 2 d AB system, J 6.5 Hz, 4H ofpyrrolidine), 1.99 (2H, m, 2H of pipH-3, H-5), 1.90-1.78 (4H, m,BzpipH-3, H-5), 1.62 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ−135.6; m/z: 629 [M+H]⁺.

Compound 444:6-(4-(4-(pyrrolidin-1-yl)benzoyl)piperidine-1-carbonyl)-N-(1-(4-(pyrrolidin-1-yl)benzyl)piperidin-4-yl)nicotinamide.¹H nmr (CDCl₃) δ 8.90 (1H, m, pyH-6), 8.12 (1H, dd, J 8.5, 2.0 Hz,pyH-4), 7.87 (2H, d, J 9.0 Hz, 2H of COC₆H₄N), 7.61 (1H, d, J 8.5 Hz,pyH-3), 7.15 (2H, d, J 9.0 Hz, 2H of CH₂C₆H₄N), 6.53 (2H, d, J 9.0 Hz,2H of 1×C₆H₄N), 6.52 (2H, d, J 8.5 Hz, 2H of 1×C₆H₄N), 6.33 (1H, d, J8.0 Hz, NH), 4.69 (1H, m, 1H of BzpipH-2, H-6), 4.00 (1H, m, pipH-4),3.90 (1H, m, 1H of BzpipH-2, H-6), 3.49 (1H, m, BzpipH-4), 3.43 (2H, s,CH₂C₆H₄N), 3.38, 3.35 (4H, 2 d AB system, J 6.5 Hz, 4H of1×pyrrolidine), 3.28, 3.26 (4H, 2 d AB system, J 6.5 Hz, 4H of1×pyrrolidine), 3.24 (1H, m, 1H of BzpipH-2, H-6), 3.08 (1H, m, 1H ofBzpipH-2, H-6), 2.88 (2H, m, 2H of pipH-2, H-6), 2.14 (2H, dd, J 11.5,9.5 Hz, 2H of pipH-2, H-6), 2.04-1.96 (10H, m, 2H of pipH-3, H-5, 4H of2×pyrrolidine), 1.90-1.78 (4H, m, BzpipH-3, H-5), 1.61 (2H, m, 2H ofpipH-3, H-5); m/z: 650 [M+H]⁺.

Compound 445:6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)-N-(piperidin-4-yl)nicotinamide(as its dihydrochloride salt). ¹H nmr (CDCl₃) δ 8.99 (1H, s, pyH-6),8.75 (3H, m, NH, NH₂), 8.30 (1H, dt, J 8.5, 2.0 Hz, pyH-4), 7.98 (2H, d,J 9.0 Hz, C₆H₄OCH₃), 7.65 (1H, d, J 8.0 Hz, pyH-3), 7.04 (2H, d, J 8.5Hz, 2H of C₆ H ₄OCH₃), 4.50 (1H, m, BzpipH-2, H-6), 4.06 (1H, m,pipH-4), 3.83 (3H, s, OCH3), 3.73 (1H, m, BzpipH-4), 3.60 (1H, m, 1H ofBzpipH-2, H-6), 3.33-3.17 (3H, m, 2H of pipH-2, H-6, 1H of BzpipH-2,H-6), 3.06-2.98 (3H, m, 2H of pipH-2, H-6, 1H of BzpipH-2, H-6),1.99-1.86 (3H, m, 3H of pipH-3, H-5, BzpipH-3, H-5), 1.77-1.65 (3H, m,3H of pipH-3, H-5, BzpipH-3, H-5), 1.60-1.49 (2H, m, 2H of pipH-3, H-5,BzpipH-3, H-5); m/z: 452 [M+H]⁺.

Compound 446:N-(1-(4-isopropoxybenzyl)piperidin-4-yl)-6-(4-(4-(pyrrolidin-1-yl)benzoyl)piperidine-1-carbonyl)nicotinamide.¹H nmr (CDCl₃) d 8.83 (1H, m, pyH-6), 8.05 (1H, dd, J 8.0, 2.0 Hz,pyH-4), 7.80 (2H, d, J 9.5 Hz, 2H of C₆H₄N), 7.54 (1H, d, J 8.0, pyH-3),7.13 (2H, d, J 9.0 Hz, 2H of C₆H₄OiPr), 6.76 (2H, d, J 9.0 Hz, 2H ofC₆H₄OiPr), 6.46 (2H, d, J 9.0 Hz, 2H of C₆H₄N), 6.28 (1H, d, J 8.0 Hz,NH), 4.63 (1H, m, 1H of BzpipH-2, H-6), 4.46 (1H, heptet, J 6.0 Hz,OCH(CH₃)₂), 3.94 (1H, m, pipH-4), 3.84 (1H, m, 1H of BzpipH-2, H-6),3.43 (1H, m, BzpipH-4), 3.39 (2H, s, CH ₂C₆H₄OiPr), 3.31, 3.29 (4H, 2 dAB system, J 6.5 Hz, 4H of pyrrolidine), 3.17 (1H, m, 1H of BzpipH-2,H-6), 3.02 (1H, m, 1H of BzpipH-2, H-6), 2.80 (2H, m, 2H of pipH-2,H-6), 2.09 (2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 1.98, 1.96 (4H, 2 d ABsystem, J 6.5 Hz, 4H of pyrrolidine), 1.92 (2H, m, 2H of pipH-3, H-5),1.87-1.67 (4H, m, 4H of BzpipH-3, H-5), 1.55 (2H, m, 2H of pipH-3, H-5);m/z: 638 [M+H]⁺.

Compound 447:N-(1-(4-cyano-3-fluorobenzyl)piperidin-4-yl)-6-(4-(4-(pyrrolidin-1-yl)benzoyl)piperidine-1-carbonyl)nicotinamide.¹H nmr (CDCl₃) δ 8.91 (1H, m, pyH-6), 8.12 (1H, dd, J 8.0, 2.0 Hz,pyH-4), 7.87 (2H, d, J 9.0 Hz, 2H of C₆H₄N), 7.56 (1H, d, J 8.0 Hz,pyH-3), 7.54 (1H, dd, J 8.0, 6.5 Hz, C₆H₃FCNH—H-5 or H-6), 7.26 (1H, d,J 10.0 Hz, C₆H₃FCNH-2), 7.22 (1H, d, J 8.5 Hz, C₆H₃FCNH-5 or H-6), 6.61(1H, d, J 7.5 Hz, NH), 6.53 (2H, d, J 8.5 Hz, 2H of C₆H₄N), 4.71 (1H, m,1H of BzpipH-2, H-6), 4.01 (1H, m, pipH-4), 3.90 (1H, m, 1H of BzpipH-2,H-6), 3.55 (2H, s, CH2C6H4N), 3.51 (1H, m, BzpipH-4), 3.38, 3.36 (4H, 2d AB system, J 6.5 Hz, 4H of pyrrolidine), 3.24 (1H, m, 1H of BzpipH-2,H-6), 3.09 (1H, m, 1H of BzpipH-2, H-6), 2.83 (2H, m, 2H of pipH-2,H-6), 2.22 (2H, dd, J 11.5, 9.5 Hz, 2H of pipH-2, H-6), 2.05, 2.03 (4H,2 d AB system, J 6.5 Hz, 4H of pyrrolinine), 2.00 (2H, m, 2H of pipH-3,H-5), 1.95-1.78 (4H, m, BzpipH-3, H-5), 1.65 (2H, m, 2H of pipH-3, H-5);¹⁹F nmr (CDCl₃) δ −106.9; m/z: 624 [M+H]⁺.

Compound 448:N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(4-(cyclopropanesulfonamido)phenoxy)piperidine-1-carbonyl)nicotinamide.¹H nmr (CDCl₃) δ 8.45 (1H, m, pyH-6), 8.08 (1H, dd, J 8.0, 2.0 Hz,pyH-4), 7.61 (1H, d, J 8.5 Hz, pyH-3), 7.54 (2H, d, J 8.5 Hz, 2H ofC₆H₄CN), 7.38 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.15 (2H, d, J 9.5 Hz, 2Hof C₆ H ₄NHSO₂), 6.82 (2H, d, J 9.0 Hz, 2H of C₆ H ₄NHSO₂), 6.10 (1H, s,NHSO₂), 6.04 (1H, d, J 7.5 Hz, NH), 4.51 (1H, m, PhOpipH-4), 3.97 (1H,m, pipH-4), 3.84 (2H, m, 2H of PhOpipH-2, H-6), 3.66 (1H, m, 1H ofPhOpipH-2, H-6), 3.46-3.38 (1H, m, 1H of PhOpipH-2, H-6), 2.76 (2H, m,2H of pipH-2, H-6), 2.36 (1H, m, cPrH-1), 2.15 (2H, dd, J 11.0, 9.5 Hz,2H of pipH-2, H-6), 2.00-1.1.86 (5H, m, 2H of pipH-3, H-5, 3H ofPhOpipH-3, H-5), 1.79 (1H, m, 1H of PhOpipH-3, H-5), 1.53 (2H, m, 2H ofpipH-3, H-5), 1.05 (2H, m, 2H of cPrH-2, H-3), 0.88 (2H, m, 2H ofcPrH-2, H-3); m/z: 644 [M+H]⁺.

Compound 449:6-(4-(4-(cyclopropanesulfonamido)phenoxy)piperidine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3-yl)nicotinamide.¹H nmr (CDCl₃) δ 9.45 (1H, s, 1×NH), 8.95 (1H, m, pyH-6), 8.44 (1H, d, J2.5 Hz, N,O-pyH-6), 8.33 (1H, dd, J 9.0, 2.5 Hz, N,O-pyH-4), 8.12 (1H,dd, J 8.5, 2.0 Hz, pyH-4), 7.44 (1H, d, J 8.0 Hz, pyH-3), 7.22 (2H, d, J9.0 Hz, 2H of C₆ H ₄NHSO₂), 7.20-7.08 (4H, m, C₆H₄F), 6.94 (1H, d, J 8.5Hz, N,O-pyH-3), 6.89 (2H, d, J 9.0 Hz, 2H of C₆ H ₄NHSO₂), 6.29 (1H, s,1×NH), 4.58 (1H, m, PhOpipH-4), 3.99-3.93 (1H, m, 1H of PhOpipH-2, H-6),3.88-3.83 (1H, m, 1H of PhOpipH-2, H-6), 3.65 (1H, m, 1H of PhOpipH-2,H-6), 3.41-3.36 (1H, m, 1H of PhOpipH-2, H-6), 2.43 (1H, m, cPrH-1),2.01-1.91 (3H, m, 3H of PhOpipH-3, H-5), 1.84 (1H, m, 1H of PhOpipH-3,H-5), 1.12 (2H, m, 2H of cPrH-2, H-3), 0.94 (2H, m, 2H of cPrH-2, H-3);¹⁹F nmr (CDCl₃) δ −118.5; m/z: 632 [M+H]⁺.

Compound 450:N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(4-(trifluoromethylsulfonyl)phenoxy)piperidine-1-carbonyl)nicotinamide.¹H nmr (CDCl₃) δ 8.91 (1H, d, J 2.0 Hz, pyH-6), 8.15 (1H, dd, J 8.0, 2.0Hz, pyH-4), 7.96 (2H, d, J 9.5 Hz, 2H of C₆H₄SO₂), 7.70 (1H, d, J 8.5Hz, pyH-3), 7.61 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.45 (2H, d, J 8.5 Hz,2H of C₆H₄CN), 7.11 (2H, d, J 9.0 Hz, 2H of C₆H₄SO₂), 6.14 (1H, d, J 7.5Hz, NH), 4.79 (1H, m, PhOpipH-4), 4.03 (1H, m, pipH-4), 3.94 (2H, m, 2Hof PhOpipH-2, H-6), 3.75 (1H, m, 1H of PhOpipH-2, H-6), 3.57 (3H, m, 1Hof PhOpipH-2, H-6, CH ₂C₆H₄CN), 2.83 (2H, m, 2H of pipH-2, H-6), 2.21(2H, dd, J 11.5, 9.5 Hz, 2H of pipH-2, H-6), 2.14-1.98 (5H, m, 2H ofpipH-3, H-5, 3H of PhOpipH-3, H-5), 1.92 (1H, m, 1H of PhOpipH-3, H-5)1.62 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −78.8; m/z: 656[M+H]⁺.

Compound 451:N-((3S,4R)-1-(4-cyanobenzyl)-3-fluoropiperidin-4-yl)-6-(4-(4-(trifluoromethylsulfonyl)phenoxy)piperidine-1-carbonyl)nicotinamide¹H nmr (CDCl₃) δ 8.91 (1H, m, pyH-6), 8.13 (1H, dd, J 8.0, 2.0 Hz,pyH-4), 7.96 (2H, d, J 8.5 Hz, 2H of C₆H₄SO₂), 7.64 (1H, d, J 8.5 Hz,pyH-3), 7.62 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.44 (2H, d, J 8.5 Hz, 2Hof C₆H₄CN), 7.11 (2H, d, J 9.0 Hz, 2H of C₆H₄SO₂), 6.64 (1H, d, J 7.5Hz, NH), 4.79 (1H, m, PhOpipH-4), 4.56 (1H, dtd, J 50.5, 9.5, 4.5 Hz,pipH-3), 4.15 (1H, m, pipH-4), 3.99-3.87 (2H, m, 2H of PhOpipH-2, H-6),3.71 (1H, m, 1H of PhOpipH-2, H-6), 4.14, 4.09 (2H, 2 d AB system, J 7.5Hz, CH2C6H4CN), 3.54 (1H, m, 1H of PhOpipH-2, H-6), 3.18 (1H, m, 1H ofpipH-2), 2.80 (1H, m, 1H of pipH-6), 2.13-2.18 (3H, m, 1H of pipH2, 1Hof pipH-5, 1H of pipH-6), 2.10 (1H, m, 1H of PhOpipH-3, H-5), 2.04 (2H,m, 2H of PhOpipH-3, H-5), 1.91 (1H, m, 1H of PhOpipH-3, H-5), 1.63 (1H,m, 1H of pipH-5); ¹⁹F nmr (CDCl₃) δ −78.8, −188.6; m/z: 674 [M+H]⁺.

Compound 452:N-((3R,4R)-1-(4-cyanobenzyl)-3-fluoropiperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide.Compound 452 was separated from the racemic mixture of Compound 349using chiral chromatography on an (R, R)-Whelk-O 1 25 cm×10 mm column(silica modified with covalently bound4-(3,5-dinitrobenzamido)tetrahydrophenanthrene), available from RegisTechnologies. The instrument was a TharSFC semi-preparative HPLC system,and elution was performed isocratically using 50% MeOH with 0.1%diethylamine in supercritical carbon dioxide at 14 mL/min at 30° C.Compound 452 was the later-eluting peak (at about 21 minutes under theconditions described above). The spectral data agree with Compound 349.Compound 452 was independently enantioselectively synthesized asdescribed in the following scheme:

The first step of the synthesis followed the method of Kwiatkowski, P.;Beeson, T. D.; Conrad, J. C.; MacMillan, D. W. C., J. Am. Chem. Soc.,2011, 133(6), 1738-1741, which is hereby incorporated herein byreference in its entirety. 9-Epi-DHQA is(1R)-((2R)-5-ethylquinuclidin-2-yl)(6-methoxyquinolin-4-yl)methanamine.The optical rotation [α] of the (3R,4S)-tert-butyl3-fluoro-4-hydroxypiperidine-1-carboxylate was −20.0° (c 0.33, CH₂Cl₂);the literature value for the corresponding (3S,4R) compound is +21.6°.See International Patent Application Publication no. WO 2010/128425.

Compound 453:N-((3S,4S)-1-(4-cyanobenzyl)-3-fluoropiperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide.Compound 453 was separated from the racemic mixture of Compound 349using chiral chromatography as described above with reference toCompound 452. Compound 452 was the earlier-eluting peak (at about 20minutes under the conditions described above). The spectral data agreewith Compound 349.

Compound 454:N-((cis)-1-(4-cyanobenzyl)-3-fluoropiperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide¹H nmr (CDCl₃) δ 8.94 (1H, d, J 2.0 Hz, pyH-6), 8.14 (1H, dd, J 8.0, 2.0Hz, pyH-4), 7.93 (2H, d, J 9.0 Hz, 2H of C₆ H ₄OCH₃), 7.59 (2H, d, J 8.5Hz, 2H of C₆H₄CN), 7.46 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 6.94 (2H, d, J9.0 Hz, 2H of C₆ H ₄OCH₃), 6.93 (1H, m, NH), 4.87 (0.5H, m, 0.5H ofpipH-3), 4.68 (1.5H, m, 0.5H of pipH-3, 1H of BzpipH-2, H-6), 4.28-4.12(1H, m, pipH-4), 3.91 (1H, m, 1H of BzpipH-2, H-6), 3.86 (3H, s, OCH3),3.64, 3.58 (2H, 2 d AB system, J 14.0 Hz, CH2C6H4CN), 3.52 (1H, m,BzpipH-4), 3.28-3.16 (2H, m, 1H of pipH-2, 1H of BzpipH-2, H-6), 3.09(1H, m, 1H of BzpipH-2, H-6), 2.91 (1H, m, 1H of pipH-6), 2.41 (0.5H, d,J 13.0 Hz, 0.5H of pipH-2), 2.26 (1.5H, m, 0.5H of pipH-2, 1H ofpipH-6), 2.10-1.98 (2H, m, 2H of pipH-5, BzpipH-3, H-5), 1.91-1.80 (4H,m, 4H of pipH-5, BzpipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −200.8 (q, J 63 Hz);m/z: 584 [M+H]⁺.

Compound 455:6-(4-(4-(cyclopropanecarbonyl)phenoxy)piperidine-1-carbonyl)-N-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)nicotinamide.¹H nmr (CDCl₃) δ 8.91 (1H, m, pyH-6), 8.13 (1H, dd, J 8.0, 2.0 Hz,pyH-4), 8.00 (2H, d, J 9.0 Hz, 2H of C₆H₄OCF₃ or C₆H₄COcPr), 7.64 (1H,d, J 8.0 Hz, pyH-3), 7.34 (2H, d, J 8.5 Hz, 2H of C₆H₄OCF₃ orC₆H₄COcPr), 7.15 (2H, d, J 8.0 Hz, 2H of C₆H₄OCF₃ or C₆H₄COcPr), 6.96(2H, d, J 9.0 Hz, 2H of C₆H₄OCF₃ or C₆H₄COcPr), 6.30 (1H, d, J 7.5 Hz,NH), 4.73 (1H, m, PhOpipH-4), 4.01 (1H, m, pipH-4), 3.92 (2H, m, 2H ofPhOpipH-2, H-6), 3.72 (1H, m, 1H of PhOpipH-2, H-6), 3.51 (3H, m, CH₂C₆H₄OCF₃, 1H of PhOpipH-2, H-6), 2.86 (2H, m, 2H of pipH-2, H-6), 2.62(1H, tt, J 7.5, 4.5 Hz, cPrH-1), 2.18 (2H, t, J 11.0 Hz, 2H of pipH-2,H-6), 2.10-1.92 (5H, m, 2H of pipH-3, H-5, 3H of PhOpipH-3, H-5), 1.87(1H, m, 1H of PhOpipH-3, H-5), 1.60 (2H, m, 2H of pipH-3, H-5), 1.21(2H, m, 2H of cPrH-2, H-3), 1.00 (2H, m, 2H of cPrH-2, H-3); ¹⁹F nmr(CDCl₃) δ −57.2; m/z: 651 [M+H]⁺.

Compound 456:N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(4-(cyclopropanecarbonyl)phenoxy)piperidine-1-carbonyl)nicotinamide.¹H nmr (CDCl₃) δ 8.91 (1H, d, J 2.0 Hz, pyH-6), 8.12 (1H, dd, J 8.5, 2.0Hz, pyH-4), 8.01 (2H, d, J 9.0 Hz, 2H of C₆H₄COcPr), 7.62 (1H, d, J 7.5Hz, pyH-3), 7.60 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.45 (2H, d, J 8.5 Hz,2H of C₆H₄CN), 6.97 (2H, d, J 9.0 Hz, 2H of C₆H₄COcPr), 6.40 (1H, d, 8.0Hz, NH), 4.73 (1H, m, PhOpipH-4), 4.03 (1H, m, pipH-4), 3.96-3.88 (2H,m, 2H of PhOpipH-2, H-6), 3.72 (1H, m, 1H of PhOpipH-2, H-6), 3.56 (2H,s, CH ₂C₆H₄CN), 3.52 (1H, m, 1H of PhOpipH-2, H-6), 2.83 (2H, m, 2H ofpipH-2, H-6), 2.62 (tt, J 7.5, 4.5 Hz, cPrH-1), 2.20 (2H, dd, J 11.5,9.5 Hz, 2H of pipH-2, H-6), 2.05-1.94 (5H, m, 2H of pipH-3, H-5, 3H ofPhOpipH-3, H-5), 1.89 (1H, m, 1H of PhOpipH-3, H-5), 1.61 (2H, m, 2H ofpipH-3, H-5), 1.21 (2H, m, 2H of cPrH-2, H-3), 1.01 (2H, m, 2H ofcPrH-2, H-3); m/z: 593 [M+H]⁺.

Compound 457:6-(4-(4-(cyclopropanecarbonyl)phenoxy)piperidine-1-carbonyl)-N-(6-(4-fluorophenoxy)pyridin-3-yl)nicotinamide.¹H nmr (CDCl₃) δ 9.63 (1H, s, NH), 8.94 (1H, m, pyH-6), 8.46 (1H, d, J2.5 Hz, N,O-pyH-6), 8.34 (1H, dd, J 8.5, 2.5 Hz, N,O-pyH-4), 8.11 (1H,dd, J 8.0, 2.0 Hz, pyH-4), 8.01 (2H, d, J 9.0 Hz, 2H of C₆H₄COcPr), 7.41(1H, d, J 8.0 Hz, pyH-3), 7.10-7.07 (4H, m, C₆H₄F), 6.96 (2H, d, J 8.5Hz, 2H of C₆H₄COcPr), 6.95 (1H, d, J 8.5 Hz, N,O-pyH-3), 4.74 (1H, m,PhOpipH-4), 4.01 (1H, m, 1H of PhOpipH-2, H-6), 3.86 (1H, m, 1H ofPhOpipH-2, H-6), 3.65 (1H, m, 1H of PhOpipH-2, H-6), 3.41 (1H, m, 1H ofPhOpipH-2, H-6), 2.62 (1H, tt, J 8.0, 4.5 Hz, cPrH-1), 2.11-1.94 (3H, m,3H of PhOpipH-3, H-5), 1.89 (1H, m, 1H of PhOpipH-3, H-5), 1.21 (2H, m,2H of cPrH-2, H-3), 1.01 (2H, m, 2H of cPrH-2, H-3); ¹⁹F nmr (CDCl₃) δ−118.5; m/z: 581 [M+H]⁺.

Compound 458:6-(4-(4-(cyclopropanecarbonyl)phenoxy)piperidine-1-carbonyl)-N-(1-(4-methoxybenzyl)piperidin-4-yl)nicotinamide.¹H nmr (CDCl₃) δ 8.90 (1H, m, pyH-6), 8.12 (1H, dd, J 8.5, 2.0 Hz,pyH-4), 8.00 (2H, d, J 9.0 Hz, 2H of C₆H₄COcPr), 7.62 (1H, d, J 8.0 Hz,pyH-3), 7.23 (2H, d, J 8.5 Hz, 2H of C₆H₄OCH₃), 6.96 (2H, d, J 9.0 Hz,2H of C₆H₄COcPr), 6.85 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 6.38 (1H, d, J7.5 Hz, NH), 4.73 (1H, m, PhOpipH-4), 4.01 (1H, m, pipH-4), 3.95-3.86(2H, m, 2H of PhOpipH-2, H-6), 3.79 (3H, s, OCH₃), 3.71 (1H, m,PhOpipH-2, H-6), 3.50 (3H, m, CH₂C₆H₄OCH₃, 1H of PhOpipH-2, H-6), 2.90(2H, m, 2H of pipH-2, H-6), 2.62 (1H, tt, J 8.0, 4.5 Hz, cPrH-1), 2.20(2H, t, J 11.0 Hz, 2H of pipH-2, H-6), 2.02 (5H, m, 2H of pipH-3, H-5,3H of PhOpipH-3, H-5), 1.88 (1H, m, 1H of PhOpipH-3, H-5), 1.21 (2H, m,2H of cPrH-2, H-3), 1.01 (2H, m, 2H of cPrH-2, H-3); m/z: 597 [M+H]⁺.

Compound 459:N-(6-(4-cyanophenoxy)pyridin-3-yl)-6-(4-(4-(methylsulfonyl)phenoxy)piperidine-1-carbonyl)nicotinamide.¹H nmr (CDCl₃) δ 9.64 (1H, s, NH), 8.96 (1H, m, pyH-6), 8.52 (1H, d, J2.5 Hz, N,O-pyH-6), 8.44 (1H, dd, J 9.0, 2.5 Hz, N,O-pyH-4), 8.12 (1H,dd, J 8.0, 2.0 Hz, pyH-4), 7.87 (2H, d, J 9.0 Hz, 2H of C₆H₄SO₂CH₃),7.68 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 7.44 (1H, d, J 8.0 Hz, pyH-3),7.23 (2H, d, J 9.5 Hz, 2H of C₆H₄CN), 7.06 (1H, m, N,O-pyH-3), 7.03 (2H,d, J 9.0 Hz, 2H of C₆H₄SO₂CH₃), 4.75 (1H, m, PhOpipH-4), 4.02 (1H, m, 1Hof PhOpipH-2, H-6), 3.88 (1H, m, 1H of PhOpipH-2, H-6), 3.66 (1H, m, 1Hof PhOpipH-2, H-6), 3.45 (1H, m, 1H of PhOpipH-2, H-6), 3.04 (3H, s,SO₂CH₃), 2.18-1.96 (3H, m, 3H of PhOpipH-3, H-5), 1.90 (1H, m, 1H ofPhOpipH-3, H-5); m/z: 598 [M+H]⁺.

Compound 460:N-(6-(4-cyanophenoxy)pyridin-3-yl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide.¹H nmr (CDCl₃) δ 9.95 (1H, s, NH), 8.93 (1H, d, J 2.0 Hz, pyH-6), 8.57(1H, d, J 2.5 Hz, N,O-pyH-6), 8.46 (1H, dd, J 8.5, 2.5 Hz, N,O-pyH-4),8.09 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.93 (2H, d, J 9.0 Hz, 2H ofC₆H₄OCH₃), 7.67 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.38 (1H, d, J 8.5 Hz,pyH-3), 7.22 (2H, d, J 8.5 Hz, 2H of C₆H₄CN), 7.06 (1H, d, J 8.5 Hz,N,O-pyH-3), 6.96 (2H, d, J 9.0 Hz, 2H of C₆ H ₄OCH₃), 4.70 (1H, m, 1H ofBzpipH-2, H-6), 3.88 (3H, s, OCH₃), 3.79 (1H, m, 1H of BzpipH-2, H-6),3.55 (1H, m, BzpipH-4), 3.24 (1H, m, 1H of BzpipH-2, H-6), 3.16 (1H, m,1H of BzpipH-2, H-6), 2.04 (1H, m, 1H of BzpipH-3, H-5), 1.93-1.82 (3H,m, 3H of BzpipH-3, H-5); m/z: 562 [M+H]⁺.

Compound 461:N-((cis)-3-fluoro-1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide.¹H nmr (CDCl₃) δ 8.96 (1H, m, pyH-6), 8.17 (1H, dd, J 8.0, 2.0 m Hz,pyH-4), 7.94 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 7.68 (1H, dd, J 8.0, 0.5Hz, pyH-3), 7.36 (2H, d, J 9.0 Hz, 2H of C₆H₄OCF₃), 7.17 (2H, d, J 8.0Hz, 2H of C₆H₄OCF₃), 6.95 (2H, d, J 9.0 Hz, 2H of C₆H₄OCH₃), 6.57 (1H,d, J 9.0 Hz, NH), 4.86 (0.5H, m, 0.5H of pipH-3), 4.68 (1.5H, m, 1H ofBzpipH-2, H-6, 0.5H of pipH-3), 4.33-4.15 (1H, m, pipH-4), 3.96 (1H, m,1H of BzpipH-2, H-6), 3.88 (3H, s, OCH₃), 3.60, 3.55 (2H, 2 d AB system,J 14.0 Hz, CH₂C₆H₄OCF₃), 3.52 (1H, m, BzpipH-4), 3.31-3.22 (2H, m, 1H ofpipH-2, 1H of BzpipH-2, H-6), 3.11 (1H, m, 1H of BzpipH-2, H-6), 2.95(1H, m, 1H of pipH-6), 2.39 (0.5H, d, J 12.5 Hz, 0.5H of pipH-2), 2.24(1.5 Hz, 0.5H of pipH-2, 1H of pipH-6), 2.05-1.97 (2H, m, 1H of pipH-5,1H of BzpipH-3, H-5), 1.93-1.81 (4H, m, 1H of pipH-5, 3H of BzpipH-3,H-5); ¹⁹F nmr (CDCl₃) δ −57.9, −200.8; m/z: 644 [M+H]⁺.

Compound 462:N-(6-(4-acetylphenoxy)pyridin-3-yl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide.¹H nmr (CDCl₃) δ 9.98 (1H, s, NH), 8.93 (1H, m, pyH-6), 8.56 (1H, d, J2.5 Hz, N,O-pyH-6), 8.42 (1H, dd, J 9.0, 2.5 Hz, N,O-pyH-4), 8.10 (1H,dd, J 8.0, 2.0 Hz, pyH-4), 7.99 (2H, d, J 9.0 Hz, 2H of C₆ H ₄COCH₃),7.93 (2H, d, J 9.0 Hz, 2H of C₆ H ₄OCH₃), 7.38 (1H, d, J 8.0 Hz, pyH-3),7.18 (2H, d, J 8.5 Hz, 2H of C₆ H ₄COCH₃), 7.03 (1H, d, J 9.0 Hz,N,O-pyH-3), 6.95 (2H, d, J 9.0 Hz, 2H of C₆ H ₄OCH₃), 7.68 (1H, m, 1H ofBzpipH-2, H-6), 3.88 (3H, s, OCH₃), 3.78 (1H, m, 1H of BzpipH-2, H-6),3.54 (1H, m, BzpipH-4), 3.23 (1H, m, 1H of BzpipH-2, H-6), 3.15 (1H, m,1H of BzpipH-2, H-6), 2.59 (3H, s, COCH₃), 2.03 (1H, m, 1H of BzpipH-3,H-5), 1.92-1.81 (3H, m, 3H of BzpipH-3, H-5); m/z: 579 [M+H]⁺.

Compound 463:N-(6-(4-cyanophenoxy)pyridin-3-yl)-6-(4-(2,4-difluorobenzoyl)piperidine-1-carbonyl)nicotinamide.¹H nmr (CDCl₃) δ 9.99 (1H, s, NH), 8.90 (1H, m, pyH-6), 8.57 (1H, d, J2.5 Hz, N,O-pyH-6), 8.46 (1H, dd, J 9.0, 2.5 Hz, N,O-pyH-4), 8.07 (1H,dd, J 8.0, 2.0 Hz, pyH-4), 7.87 (1H, dt, J 6.5, 8.5 Hz, C₆H₃F₂H-6), 7.68(2H, d, J 9.0 Hz, 2H of C₆H₄CN), 7.34 (1H, d, J 8.0 Hz, pyH-3), 7.22(2H, d, J 9.0 Hz, 2H of C₆H₄CN), 7.05 (1H, d, J 9.0 Hz, N,O-pyH-3), 7.00(1H, m, C₆H₃F₂H-3 or H-5), 6.89 (1H, ddd, J 11.0, 8.5, 2.5 Hz, C₆H₃F₂H-3or H-5), 4.67 (1H, m, 1H of BzpipH-2, H-6), 3.75 (1H, m, 1H of BzpipH-2,H-6), 3.42 (1H, m, BzpipH-4), 3.24-3.09 (2H, m, 2H of BzpipH-2, H-6),2.09 (1H, m, 1H of BzpipH-3, H-5), 1.91-1.72 (3H, m, 3H of BzpipH-3,H-5); ¹⁹F nmr (CDCl₃) δ −101.1, −106.5; m/z: 568 [M+H]⁺.

Compound 464:N-(6-(4-acetylphenoxy)pyridin-3-yl)-6-(4-(2,4-difluorobenzoyl)piperidine-1-carbonyl)nicotinamide.¹H nmr (CDCl₃) δ 9.62 (1H, s, NH), 8.94 (1H, m, pyH-6), 8.41 (1H, dd, J8.0, 2.5 Hz, N,O-pyH-4), 8.11 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 8.01 (2H,d, J 9.0 Hz, 2H of C₆ H ₄COCH₃), 7.87 (1H, dt, J 6.5, 8.5 Hz,C₆H₃F₂H-6), 7.42 (1H, d, J 8.0 Hz, pyH-3), 7.19 (2H, d, J 9.0 Hz, 2H ofC₆ H ₄COCH₃), 7.04 (1H, d, J 9.0 Hz, N,O-pyH-3), 6.99 (1H, m, C₆H₃F₂H-3or H-5), 6.89 (1H, ddd, J 11.0, 8.4, 2.0 Hz, C₆H₃F₂H-3 or H-5), 4.67(1H, m, 1H of BzpipH-2, H-6), 3.79 (1H, m, 1H of BzpipH-2, H-6), 3.41(1H, m, BzpipH-4), 3.25-3.08 (2H, m, 2H of BzpipH-2, H-6), 2.60 (3H, s,COCH₃), 2.08 (1H, m, 1H of BzpipH-3, H-5), 1.91-1.74 (3H, m, 3H ofBzpipH-3, H-5); ¹⁹F nmr (CDCl₃) δ−101.3, −106.5; m/z: 585 [M+H]⁺.

Compound 465:6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)-N-(6-(4-(methylsulfonyl)phenoxy)pyridin-3-yl)nicotinamide.¹H nmr (CDCl₃) δ 9.92 (1H, s, NH), 8.94 (1H, m, pyH-6), 8.59 (1H, d, J2.5 Hz, N,O-pyH-6), 8.45 (1H, dd, J 9.0, 2.5 Hz, N,O-pyH-4), 8.11 (1H,dd, J 8.0, 2.0 Hz, pyH-4), 7.95 (2H, d, J 8.5 Hz, 2H of C₆ H ₄OCH₃ or C₆H ₄SO₂CH₃), 7.93 (2H, d, J 9.0 Hz, 2H of C₆ H ₄OCH₃ or C₆ H ₄SO₂CH₃),7.39 (1H, d, J 8.0 Hz, pyH-3), 7.30 (2H, d, J 9.0 Hz, 2H of C₆ H₄SO₂CH₃), 7.07 (1H, d, J 9.0 Hz, N,O-pyH-3), 6.96 (2H, d, J 9.0 Hz, 2Hof C₆ H ₄OCH₃), 7.69 (1H, m, 1H of BzpipH-2, H-6), 3.88 (3H, s, OCH₃),3.79 (1H, m, 1H of BzpipH-2, H-6), 3.55 (1H, m, BzpipH-4), 3.29-3.13(2H, m, 2H of BzpipH-2, H-6), 3.07 (3H, s, SO₂CH₃), 2.03 (1H, m, 1H, m,1H of BzpipH-3, H-5), 1.93-1.81 (3H, m, 3H of BzpipH-3, H-5); m/z: 615[M+H]⁺.

Compound 466:6-(4-(2,4-difluorobenzoyl)piperidine-1-carbonyl)-N-(6-(4-(methylsulfonyl)phenoxy)pyridin-3-yl)nicotinamide.¹H nmr (CDCl₃) δ 10.00 (1H, s, NH), 8.91 (1H, m, pyH-6), 8.60 (1H, d, J2.5 Hz, N,O-pyH-6), 8.46 (1H, dd, J 8.5, 2.5 Hz, N,O-pyH-4), 8.07 (1H,dd, J 8.0, 2.0 Hz, pyH-4), 7.96 (2H, d, J 8.5 Hz, 2H of C₆ H ₄SO₂CH₃),7.87 (1H, dt, J 6.5, 9.0 Hz, C₆H₃F₂H-6), 7.35 (1H, d, J 8.0 Hz, pyH-3),7.30 (2H, d, J 8.5 Hz, 2H of C₆ H ₄SO₂CH₃), 7.07 (1H, d, J 8.5 Hz,N,O-pyH-3), 6.99 (1H, m, C₆H₃F₂H-3 or H-5), 6.89 (1H, ddd, J 11.0, 8.5,2.0 Hz, C₆H₃F₂H-3 or H-5), 4.67 (1H, m, 1H of BzpipH-2, H-6), 3.75 (1H,m, 1H of BzpipH-2, H-6), 3.42 (1H, m, BzpipH-4), 3.25-3.09 (2H, m, 2H ofBzpipH-2, H-6), 3.07 (3H, s, SO₂CH₃), 2.09 (1H, m, 1H of BzpipH-3, H-5),1.91-1.75 (3H, m, 3H of BzpipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −101.2,−106.5; m/z: 621 [M+H]⁺.

Compound 467:N-(6-(4-fluorophenylsulfonyl)pyridin-3-yl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide.¹H nmr (CDCl₃) δ 10.11 (1H, s, NH), 8.98 (1H, d, J 2.5 Hz, N,O-pyH-6),8.90 (1H, m, pyH-6), 8.63 (1H, dd, J 8.5, 2.5 Hz, N,O-pyH-4), 8.20 (1H,d, J 8.5 Hz, N,O-pyH-3), 8.10-8.06 (3H, m, pyH-4, 2H of C₆H₄F), 7.94(2H, d, J 9.0 Hz, 2H of C₆ H ₄OCH₃), 7.39 (1H, d, J 8.5 Hz, pyH-3), 7.20(2H, t, J 8.5 Hz, 2H of C₆H₄F), 6.97 (2H, d, J 9.0 Hz, 2H of C₆ H₄OCH₃), 4.69 (1H, m, 1H of BzpipH-2, H-6), 3.89 (3H, s, OCH₃), 3.76 (1H,m, 1H of BzpipH-2, H-6), 3.55 (1H, m, BzpipH-4), 3.21 (2H, m, 2H ofBzpipH-2, H-6), 2.04 (1H, m, 1H of BzpipH-3, H-5), 1.94-1.76 (3H, m, 3Hof BzpipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −103.6; m/z: 603 [M+H]⁺ (found[M+H]⁺, 603.1692, C₃₁H₂₇FN₄O₆S requires [M+H]⁺ 603.1708).

Compound 468:N-(5-(4-cyanophenoxy)pyridin-2-yl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamide.¹H nmr (CDCl₃) δ 9.32 (1H, s, NH), 8.97 (1H, d, J 2.0 Hz, pyH-6), 8.50(1H, d, J 2.5 Hz, N,O-pyH-6), 8.41 (1H, dd, J 9.0, 2.5 Hz, N,O-pyH-4),8.16 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.94 (2H, d, J 9.0 Hz, 2H of C₆ H₄OCH₃), 7.68 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 7.50 (1H, d, J 8.0 Hz,pyH-3), 7.23 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 7.07 (1H, d, J 9.0 Hz,N,O-pyH-3), 6.96 (2H, d, J 8.5 Hz, 2H of C₆ H ₄OCH₃), 4.69 (1H, m, 1H ofBzpipH-2, H-6), 3.89 (3H, s, OCH₃), 3.85 (1H, m, 1H of BzpipH-2, H-6),3.55 (1H, m, BzpipH-4), 3.22-3.10 (2H, m, 2H of BzpipH-2, H-6), 2.02(1H, m, 1H of BzpipH-3, H-5), 1.93-1.80 (3H, m, 3H of BzpipH-3, H-5);m/z: 562 [M+H]⁺.

Compound 469:N-(5-(4-cyanophenoxy)pyridin-2-yl)-6-(4-(2,4-difluorobenzoyl)piperidine-1-carbonyl)nicotinamide.¹H nmr (CDCl₃) δ 9.72 (1H, s, NH), 8.93 (1H, m, pyH-6), 8.54 (1H, d, J2.5 Hz, N,O-pyH-6), 8.44 (1H, dd, J 9.0, 3.0 Hz, N,O-pyH-4), 8.10 (1H,dd, J 8.0, 2.0 Hz, pyH-4), 7.88 (1H, dt, J 6.5, 9.0 Hz, C₆H₃F₂H-6), 7.68(2H, d, J 9.0 Hz, 2H of C₆H₄CN), 7.40 (1H, d, J 8.0 Hz, pyH-3), 7.23(2H, d, J 9.0 Hz, 2H of C₆H₄CN), 7.06 (1H, d, J 9.0 Hz, N,O-pyH-3), 7.00(1H, m, C₆H₃F₂H-3 or H-5), 6.90 (1H, ddd, J 11.0, 8.5, 2.0 Hz, C₆H₃F₂H-3or H-5), 4.67 (1H, m, 1H of BzpipH-2, H-6), 3.77 (1H, m, 1H of BzpipH-2,H-6), 3.42 (1H, m, BzpipH-4), 3.25-3.08 (2H, m, 2H of BzpipH-2, H-6),2.09 (1H, m, 1H of BzpipH-3, H-5), 1.91-1.75 (3H, m, 3H of BzpipH-3,H-5); ¹⁹F nmr (CDCl₃) δ −101.2, −106.5; m/z: 568 [M+H]⁺.

Compound 470:6-(4-(4-fluorophenylsulfonyl)piperidine-1-carbonyl)-N-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)nicotinamide.¹H nmr (CDCl₃) δ 8.88 (1H, m, pyH-6), 8.11 (1H, dd, J 8.5, 2.0 Hz,pyH-4), 7.89 (2H, dd, J 9.0, 5.0 Hz, 2H of C₆H₄F), 7.63 (1H, d, J 7.5Hz, pyH-3), 7.34 (2H, d, J 8.5 Hz, 2H of C₆H₄OCF₃), 7.26 (2H, t, J 8.5Hz, 2H of C₆H₄F), 7.16 (2H, d, J 7.5 Hz, 2H of C₆H₄OCF₃), 6.31 (1H, d, J8.0 Hz, NH), 4.83 (1H, m, 1H of BzpipH-2, H-6), 4.13 (1H, m, 1H ofBzpipH-2, H-6), 4.01 (1H, m, pipH-4), 3.52 (2H, s, CH2C6H4OCF3), 3.16(1H, tt, J 12.0, 3.5 Hz, BzpipH-4), 3.04 (1H, m, 1H of BzpipH-2, H-6),2.87-2.75 (3H, m, 2H of pipH-2, H-6, 1H of BzpipH-2, H-6), 2.17 (2H, t,J 11.5 Hz, 2H of pipH-2, H-6), 2.01 (4H, m, 2H of pipH-3, H-5, 2H ofBzpipH-3, H-5), 1.79 (2H, qd, J 12.5, 4.0 Hz, 2H of BzpipH-3, H-5), 1.59(2H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ−57.9, −102.6; m/z: 649[M+H]⁺.

Compound 471:N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(4-fluorophenylsulfonyl)piperidine-1-carbonyl)nicotinamide.¹H nmr (CDCl₃) δ 8.88 (1H, d, J 2.0 Hz, pyH-6), 8.12 (1H, dd, J 8.0, 2.0Hz, pyH-4), 7.89 (dd, J 9.0, 5.0 Hz, 2H of C₆H₄F), 7.63 (1H, m, pyH-3),7.61 (2H, d, J 8.0 Hz, 2H of C₆H₄CN), 7.45 (2H, d, J 8.0 Hz, 2H ofC₆H₄CN), 7.27 (2H, t, J 8.5 Hz, 2H of C₆H₄F), 6.36 (1H, d, J 7.5 Hz,NH), 4.83 (1H, m, 1H of BzpipH-2, H-6), 4.13 (1H, m, 1H of BzpipH-2,H-6), 4.01 (1H, m, pipH-4), 3.56 (2H, s, CH ₂C₆H₄CN), 3.17 (1H, tt, J12.0, 4.0 Hz, BzpipH-4), 3.04 (1H, t, J 12.0 Hz, 1H of BzpipH-2, H-6),2.85-2.74 (3H, m, 2H of pipH-2, H-6, 1H of BzpipH-2, H-6), 2.20 (2H, dd,J 11.5, 9.5 Hz, 2H of pipH-2, H-6), 2.11-1.95 (4H, m, 2H of pipH-3, H-5,2H of BzpipH-3, H-5), 1.80 (qd, J 12.5, 4.0 Hz, 2H of BzpipH-3, H-5),1.60 (2H, m, 2H of pipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −102.6; m/z: 590[M+H]⁺.

Compound 472:N-(6-(4-cyanophenoxy)pyridin-3-yl)-6-(4-(4-fluorophenylsulfonyl)piperidine-1-carbonyl)nicotinamide.¹H nmr (CDCl₃) δ 9.61 (1H, s, NH), 8.92 (1H, d, J 2.0 Hz, pyH-6), 8.49(1H, d, J 2.5 Hz, N,O-pyH-6), 8.42 (1H, dd, J 9.0, 2.5 Hz, N,O-pyH-4),8.11 (1H, dd, J 8.0, 2.0 Hz, pyH-4), 7.89 (2H, dd, J 9.0, 5.0 Hz, 2H ofC₆H₄F), 7.69 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 7.44 (1H, d, J 8.0 Hz,pyH-3), 7.27 (2H, m, 2H of C₆H₄F), 7.23 (2H, d, J 8.5 Hz, 2H of C₆H₄CN),7.06 (1H, d, J 8.5 Hz, N,O-pyH-3), 4.83 (1H, m, 1H of BzpipH-2, H-6),3.96 (1H, m, 1H of BzpipH-2, H-6), 3.17 (1H, m, BzpipH-4), 3.09 (1H, m,1H of BzpipH-2, H-6), 2.84 (1H, m, 1H of BzpipH-2, H-6), 2.10 (1H, d, J12.0 Hz, 1H of BzpipH-3, H-5), 1.99 (1H, d, J 11.5 Hz, 1H of BzpipH-3,H-5), 1.82 (2H, m, 2H of BzpipH-3, H-5); ¹⁹F nmr (CDCl₃) δ −102.2; m/z:586 [M+H]⁺.

Compound 473:N-(6-(4-acetylphenoxy)pyridin-3-yl)-6-(4-(4-fluorophenylsulfonyl)piperidine-1-carbonyl)nicotinamide.¹H nmr (CDCl₃) δ 9.31 (1H, s, NH), 8.95 (1H, m, pyH-6), 8.45 (1H, d, J2.5 Hz, N,O-pyH-6), 8.38 (1H, dd, J 9.0, 2.5 Hz, N, O-pyH-4), 8.14 (1H,dd, J 8.5, 2.0 Hz, pyH-4), 8.02 (2H, d, J 9.0 Hz, 2H of C₆H₄Ac), 7.89(2H, dd, J 9.0, 5.0 Hz, 2H of C₆H₄F), 7.49 (1H, d, J 8.0 Hz, pyH-3),7.27 (2H, t, J 8.5 Hz, 2H of C₆H₄F), 7.20 (2H, d, J 9.0 Hz, 2H ofC₆H₄Ac), 7.05 (1H, d, J 9.0 Hz, N,O-pyH-3), 4.83 (1H, m, 1H of BzpipH-2,H-6), 4.01 (1H, m, 1H of BzpipH-2, H-6), 3.17 (1H, m, BzpipH-4), 3.06(1H, m, 1H of BzpipH-2, H-6), 2.83 (1H, m, 1H of BzpipH-2, H-6), 2.60(3H, s, COCH₃), 2.10 (1H, d, J 12.5 Hz, 1H of BzpipH-3, H-5), 2.01 (1H,d, J 12.5 Hz, 1H of BzpipH-3, H-5), 1.82 (2H, qd, J 12.5, 4.0 Hz, 2H ofBzpipH-3, H-5); ¹⁹F nmr (CDCl₃) δ−102.3; m/z: 603 [M+H]⁺(found [M+H]⁺,603.1689, C₃₁H₂₇FN₄O₆S requires [M+H]⁺ 603.1708).

Compound 474:6-(4-(4-fluorophenylsulfonyl)piperidine-1-carbonyl)-N-(1-(4-methoxybenzyl)piperidin-4-yl)nicotinamide.¹H nmr (CDCl₃) δ 8.90 (1H, m, pyH-6), 8.13 (1H, dd, J 8.5, 2.0 Hz,pyH-4), 7.91 (2H, dd, J 9.0, 5.0 Hz, 2H of C₆H₄F), 7.66 (1H, d, J 8.0Hz, pyH-3), 7.29 (2H, t, J 9.0 Hz, 2H of C₆H₄F), 7.24 (2H, d, J 8.5 Hz,2H of C₆ H ₄OCH₃), 6.88 (2H, d, J 8.5 Hz, 2H of C₆ H ₄OCH₃), 6.31 (1H,d, J 8.0 Hz, NH), 4.85 (1H, m, 1H of BzpipH-2, H-6), 4.16 (1H, m, 1H ofBzpipH-2, H-6), 4.02 (1H, m, pipH-4), 3.83 (3H, s, OCH₃), 3.48 (2H, s,CH ₂C₆H₄OCH₃), 3.19 (1H, tt, J 12.0, 3.5 Hz, BzpipH-4), 3.07 (1H, t, J12.0 Hz, 1H of BzpipH-2, H-6), 2.90-2.77 (3H, m, 2H of pipH-2, H-6, 1Hof BzpipH-2, H-6), 2.17 (2H, dd, J 11.5, 10.0 Hz, 2H of pipH-2, H-6),2.03 (4H, m, 2H of pipH-3, H-5, 2H of BzpipH-3, H-5), 1.81 (2H, qd, J12.5, 4.0 Hz, 2H of BzpipH-3, H-5), 1.60 (2H, m, 2H of pipH-3, H-5); ¹⁹Fnmr (CDCl₃) δ −102.6; m/z: 595 [M+H]⁺.

Compound 475:6-(4-(4-fluorophenylsulfonyl)piperidine-1-carbonyl)-N-(1-(3-methoxybenzyl)piperidin-4-yl)nicotinamide.¹H nmr (CDCl₃) δ 8.88 (1H, d, J 2.0 Hz, pyH-6), 8.11 (1H, dd, J 8.5, 2.0Hz, pyH-4), 7.88 (2H, dd, J 9.0, 5.0 Hz, 2H of C₆H₄F), 7.62 (1H, d, J8.0 Hz, pyH-3), 7.29-7.20 (3H, m, 2H of C₆ H ₄F, 1H of C₆H₄OCH₃),6.91-6.88 (2H, m, 2H of C₆ H ₄OCH₃), 6.79 (1H, m, 1H of C₆ H ₄OCH₃),6.35 (1H, d, J 7.5 Hz, NH), 4.83 (1H, m, 1H of BzpipH-2, H-6), 4.12 (1H,m, 1H of BzpipH-2, H-6), 4.03 (1H, m, pipH-4), 3.81 (3H, s, OCH₃), 3.49(2H, s, CH ₂C₆H₄OCH₃), 3.16 (1H, tt, J 12.0, 3.5 Hz, BzpipH-4), 3.04(1H, t, J 11.5 Hz, 1H of BzpipH-2, H-6), 2.88-2.74 (3H, m, 2H of pipH-2,H-6, 1H of BzpipH-2, H-6), 2.16 (2H, t, J 11.5 Hz, 2H of pipH-2, H-6),2.01 (4H, m, 2H of pipH-3, H-5, 2H of BzpipH-3, H-5), 1.78 (2H, qd, J12.5, 4.5 Hz, 2H of BzpipH-3, H-5), 1.59 (2H, m, 2H of pipH-3, H-5); ¹⁹Fnmr (CDCl₃) δ −102.6; m/z: 595 [M+H]⁺.

Compound 476:N-(6-(4-cyanophenoxy)pyridin-3-yl)-6-(4-(4-fluorobenzyl)piperazine-1-carbonyl)nicotinamide.¹H nmr (CDCl₃) δ 9.87 (1H, s, NH), 8.89 (1H, m, pyH-6), 8.54 (1H, d, J2.5 Hz, N,O-pyH-6), 8.44 (1H, dd, J 9.0, 2.5 Hz, N,O-pyH-4), 8.06 (1H,dd, J 8.0, 2.0 Hz, pyH-4), 7.68 (2H, d, J 9.0 Hz, 2H of C₆H₄CN), 7.35(1H, d, J 7.5 Hz, pyH-3), 7.25 (2H, m, 2H of C₆H₄F), 7.22 (2H, d, J 8.5Hz, 2H of C₆H₄CN), 7.03 (2H, t, J 8.5 Hz, 2H of C₆H₄F), 6.99 (1H, d, J8.5 Hz, N,O-pyH-3), 3.83 (2H, m, 2H of piz), 3.50 (2H, s, CH ₂C₆H₄F),3.42, 3.41 (2H, 2 d AB system, J 4.5 Hz, 2H of piz), 2.55, 2.53 (2H, 2 dAB system, J 4.5 Hz, 2H of piz), 2.40, 2.38 (2H, 2 d AB system, J 4.5Hz, 2H of piz); ¹⁹F nmr (CDCl₃) δ −115.2; m/z: 537 [M+H]⁺.

Compound 491:N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(4-(4-fluorobenzyl)piperazin-1-yl)pyridazine-3-carboxamide.Compound 491 was prepared as follows:

Step 1

6-Chloropyridazine-3-carboxylic acid (0.96 g, 6.2 mMol) was dissolved indichloromethane (20 mL) and treated with4-amino-1-(4-cyanobenzyl)piperidine dihydrochloride (1.79 g, 6.2 mMol),HATU (2.37 g, 6.2 mMol) and DIEA (3.6 mL, 3.3 eq.). The reaction stirredat RT for 3d. The reaction mixture was diluted with dichloromethane andwashed with saturated aqueous sodium bicarbonate and brine and thendried over anhydrous sodium sulfate and concentrated under reducedpressure.

The crude product was purified by flash chromatography on silica gel,eluting with 2% methanol in dichloromethane.

¹H NMR (300 MHz, CDCl₃) δ 8.26 (d, J 8.8 Hz, 1H), 7.96 (d, J 10.0 Hz,1H, NH), 7.68 (d, J 8.8 Hz, 1H), 7.61 (d, J 8.2 Hz, 2H), 7.46 (d, J 8.0Hz, 2H), 4.02 (m, 1H), 3.15 (m, 2H), 2.81 (m, 2H), 2.29 (m, 2H), 2.12(m, 2H); m/z=356.05 (M+H)⁺; m/z=354.11 (M−H)⁺

Step 2

The product from step 1 (109 mg, 0.306 mMol) was dissolved in CH₃CN (3mL) and treated with 4-Fluorobenzylpiperazine (1.2 eq.),tetrabutylammonium iodide (24 mg) and DBU (100 μl). The reaction mixturewas then heated at 82° C. for 1.5 h. The reaction mixture wasconcentrated to dryness and purified by silica gel radial chromatographyeluting with 5% methanol in dichloromethane to give Compound 491. ¹H NMR(300 MHz, CDCl₃) δ 7.94 (dd, J 9.6, 1.4 Hz, 1H), 7.84 (d, J 8.3 Hz, 1H,NH), 7.58 (d, J 8.0 Hz, 2H), 7.43 (d, J 8.3 Hz, 2H), 7.26-7.30 (m, 2H),6.92-7.02 (m, 3H), 3.97 (m, 1H), 3.73 (m, 4H), 3.52 (s, 2H), 3.49 (s,2H), 3.12 (m, 2H), 2.77 (m, 2H), 2.54 (m, 4H), 2.20 (m, 2H), 1.97 (m,2H); m/z=514.18 (M+H)⁺;

For use in the synthesis of Compound 125,1-(4-fluorobenzyl)-2,2-dimethylpiperazine was synthesized. To a solutionof piperazin-2-one (0.500 g, 5.00 mmol, 1.0 eq) in dichloromethane (50mL) was added trityl chloride (1.533 g, 5.50 mmol, 1.1 eq). The reactionwas stirred at room temperature for 18 hours before diluting with CH₂Cl₂(50 mL). The reaction was washed with NaHCO₃ (100 mL) and brine (100mL), dried (Na₂SO₄) and concentrated under reduced pressure to yield4-tritylpiperazin-2-one as a white foam, which was used without furtherpurification; ¹H nmr (CDCl₃) 7.48 (6H, d, J 7.5 Hz, 6H of trityl), 7.28(6H, m, 6H of trityl), 7.18 (3H, m, 3H of trityl), 5.95 (1H, m, NH),3.45 (2H, br s, 2H of oxopip), 3.06 (2H, s, 2H of oxopip), 2.46 (2H, brs, 2H of oxopip). A suspension of the 4-tritylpiperazin-2-one (0.405 g,1.18 mmol, 1.0 eq) in tetrahydrofuran (11 mL) was cooled to 0° C. and4-fluorobenzyl bromide (0.246 g, 0.16 mL, 1.30 mmol, 1.1 eq) was addedfollowed by sodium hydride (0.057 g of a 60% suspension in oil, 1.42mmol, 1.2 eq). Dimethylformamide (3 mL) was added to aid dissolution.The reaction mixture was allowed to warm to room temperature withstirring for 14 hours. Additional 4-fluorobenzyl bromide (0.16 mL, 1.1eq) and sodium hydride (0.057 g, 1.2 eq) was added and the reactionstirred at room temperature for 3 hours and 60° C. for 15 hours. Thereaction was cooled and partitioned between EtOAc (50 mL) and water (50mL). The organic phase was washed with brine (50 mL), water (50 mL) andbrine (50 mL), dried (Na₂SO₄) and concentrated under reduced pressure.MPLC (10→30% EtOAc-hexane, 0→15 min then 30→70% EtOAc-hexane 15→25 min)yielded 4-tritylpiperazin-2-one as a white solid (0.374 g, 70%); ¹H nmr(CDCl₃) 7.48 (6H, d, J 7.5 Hz, 3×2H of C₆H₅), 7.28 (6H, t, J 7.5 Hz,3×2H of C₆H₅), 7.23-7.15 (5H, m, 3×1H of C₆H₅, 2H of C₆H₄F), 7.01 (2H,t, J 8.5 Hz, 2H of C₆H₄F), 4.78 (2H, s, CH₂C₆H₄F), 3.31 (2H, t, J 5.5Hz, 2H of oxopip), 3.15 (2H, s, 2H of oxopip), 2.43 (2H, m, 2H ofoxopip); m/z 451 [M+H]⁺. A solution of the 4-tritylpiperazin-2-one(0.165 g, 0.367 mmol, 1.0 eq) and di-t-butylpyridine (0.097 mL, 0.440mmol, 1.2 eq) in dichloromethane (3.5 mL) was cooled to −78° C.Trifluoromethanesulfonic acid (0.074 mL, 0.440 mmol, 1.2 eq) was addedand the reaction stirred at −78° C. for 45 minutes before addingmethylmagnesium bromide (0.79 mL of a 1.4M solution in toluene, 1.100mmol, 3.0 eq). The reaction mixture was allowed to stir at −78° C. for 2hours and warmed to 0° C. over 2 hours before quenching with NH₄Cl (3mL). The reaction was partitioned between NH₄Cl (50 mL) and CH₂Cl₂ (70mL). The aqueous phase was extracted with CH₂Cl₂ (2×50 mL) and thecombined organics dried (Na₂SO₄) before concentrating under reducedpressure. MPLC (10→30% EtOAc-hexane, 5→18 min) yielded1-(4-fluorobenzyl)-2,2-dimethyl-4-tritylpiperazine (0.126 g, 74%) as awhite solid; m/z 451 [M+H]⁺. To a solution of the1-(4-fluorobenzyl)-2,2-dimethyl-4-tritylpiperazine (0.126 g, 0.272 mmol,1.0 eq) in dichloromethane (3.0 mL) was added hydrogen chloride (0.27 mLof a 4M solution in dioxane, 1.086 mmol, 4.0 eq). The reaction wasstirred at room temperature for 4 hours. Further hydrogen chloride (0.27mL of a 4M solution in dioxane, 1.086 mmol, 4.0 eq) was added and thereaction stirred at room temperature for 1 hour before concentratingunder reduced pressure. The residue was tritutated with Et₂O (2×10 mL)to yield 1-(4-fluorobenzyl)-2,2-dimethylpiperazine as a white solid,which was dried under vacuum and used without further purification; ¹Hnmr (CD₃OD) 7.62 (2H, m, 2H of C₆H₄F), 7.23 (2H, t, J 8.5 Hz, 2H ofC₆H₄F), 3.53 (2H, s, 2H of piz), 3.44 (4H, m, 4H of piz), 1.68 (6H, s,C(CH₃)₂); m/z 223 [M+H]⁺. Syntheses of gem-dimethyl compounds are alsogenerally described in Xiao, K-J.; Luo, J-M.; Ye, K-Y.; Wang, Y.; Huang,P-Q. Angew. Chem. Int. Ed. 2010, 49, 3037-3040.

Synthesis of 1-tent-Butyloxycarbonyl-4-N-methylaminopiperidine

To a solution of 1-tert-butyloxycarbonyl-4-oxopiperidine (0.45 g, 2.26mmol, 1.0 eq) in dichloromethane (20 mL) was added methylamine (2.26 mLof a 2M solution in tetrahydrofuran, 4.52 mmol, 2.0 eq). Afterequilibrating at room temperature for 10 minutes, sodiumtriacetoxyborohydride (0.72 g, 3.39 mmol, 1.5 eq) was added and thereaction stirred at room temperature for 30 minutes. Rochelle's salt (20mL) was added and the reaction stirred for 1 hour before adding NaHCO₃(50 mL). The organics were extracted with CH₂Cl₂ (2×100 mL), combined,washed with brine (50 mL), dried (Na₂SO₄) and concentrated under reducedpressure to yield the title compound as a colourless oil; ¹H nmr (CDCl₃)δ 4.03 (2H, m), 2.79 (2H, t, J 12.0 Hz), 2.50 (1H, tt, J 12.0, 3.0 Hz),2.43 (3H, s), 1.85 (2H, m), 1.47 (9H, s,), 1.22 (2H, m); m/z: 215[M+H]⁺.

Coupling of the 4-N-methylpiperidine

To a mixture of 1-tert-butyloxycarbonyl-4-N-methylaminopiperidine (0.136g, 0.636 mmol, 1.0 eq) and the pyridine carboxylic acid (0.231 g, 0.636mmol, 1.0 eq) in dimethylformamide (6 mL) was added triethylamine (0.13mL, 0.953 mmol, 1.5 eq) followed by HATU (0.214 g, 0.636 mmol, 1.0 eq).The reaction was stirred at room temperature for 4 hours beforepartitioning between EtOAc (100 mL) and NaHCO3-water (1:1, 100 mL). Theorganics were further washed with brine (100 mL), water (100 mL) andbrine (100 mL) before drying (Na₂SO₄) and concentrating under reducedpressure. MPLC (0 10% MeOH—CH₂Cl₂) yielded the coupled material (0.215g, 61%) as a white foam; ¹H nmr (CDCl₃) δ 8.60 (1H, s, pyH-6), 7.92 (2H,d, J 9.0 Hz, 2H of C₆H₄OCH₃), 7.80 (1H, d, J 9.0 Hz, pyH-3 or pyH-6),7.67 (1H, d, J 9.0 Hz, pyH-3 or pyH-4), 6.94 (2H, d, J 9.0 Hz, 2H ofC₆H₄OCH₃), 4.63 (1H, m, 1H of BzpipH-2, H-6), 4.23 (1H, m, pipH-4), 3.98(1H, m, 1H of BzpipH-2, H-6), 3.86 (3H, s, OCH₃), 3.52 (1H, m,BzpipH-4), 3.25 (1H, m, 1H of BzpipH-2, H-6), 3.09 (1H, m, 1H ofBzpipH-2, H-6), 2.97 (1H, m, 1H of pipH-2, H-3, H-5, H-6), 2.82 (3H, brs, NCH₃), 2.55 (1H, m, 1H of pipH-2, H-3, H-5, H-6), 1.97 (1H, m, 1H ofpipH-2, H-3, H-5, H-6, BzpipH-3, H-5), 1.92-1.66 (9H, m, 9H of pipH-2,H-3, H-5, H-6, BzpipH-3, H-5), 1.45 (9H, s, C(CH₃)₃); m/z: 565 [M+H]⁺.

Synthesis of 1-tert-Butyloxycarbonyl-3,3-difluoro-4-aminopiperidine1-tert-Butyloxycarbonyl-3,3-difluoro-4-benzylaminopiperidine

To a solution of 1-tert-butyloxycarbonyl-3,3-difluoro-4-oxopiperidine(Synthonix, 0.100 g, 0.426 mmol, 1.0 eq) in dichloromethane (1.5 mL) wasadded benzylamine (0.070 mL, 0.638 mmol, 1.5 eq) followed by sodiumtriacetoxyborohydride (0.180 g, 0.851 mmol, 2.0 eq). The reaction wasstirred at room temperature for 16 hours before adding Rochelle's salt(2 mL) and stirring for 1 hour. The reaction mixture was partitionedbetween NaHCO₃ (50 mL) and CH₂Cl₂ (50 mL). The aqueous phase wasextracted with CH₂Cl₂ (2×50 mL). The combined organics were washed withbrine (50 mL), dried (Na₂SO₄) and concentrated under reduced pressure.MPLC (30→70% EtOAc-hexane) yielded the title compound (0.045 g, 32%) asa colourless oil; ¹H nmr (CDCl₃) δ 7.33 (4H, m, 4H of C₆H₅), 7.27 (1H,m, 1H of C₆H₅), 4.02 (1H, m), 3.92 (2H, s, CH₂C₆H₅), 3.76 (1H, m), 3.32(1H, ddd, J 21.5, 14.0, 4.5 Hz), 3.11 (1H, m), 2.97 (1H, m), 1.90 (1H,m), 1.67-1.59 (1H, m), 1.46 (9H, s, C(CH₃)₃); ¹⁹F nmr (CDCl₃) δ −109.0(dd, J 243.0, 115.5 Hz), −119.5 (d, J 251.0 Hz); m/z: 327 [M+H]⁺.

1-tert-Butyloxy-3,3-difluoro-4-aminopiperidine

Palladium hydroxide (approx. 0.030 g) was added to a solution of thebenzylaminopiperidine (0.045 g, 0.138 mmol) in ethanol (3.0 mL). Theflask was purged with hydrogen and the reaction stirred under anatmosphere of hydrogen for 2 hours. The flask was purged with nitrogenand the reaction filtered through celite, eluting with 5% MeOH—CH₂Cl₂(4×5 mL). The filtrate was concentrated under reduced pressure to yieldthe title compound as a colourless oil, which was used withoutpurification;

Coupling of the 3,3-difluoro-4-aminopiperidine to the pyridinecarboxylic acid

To a solution of the difluoroaminopiperidine (0.035 g, 0.148 mmol, 1.0eq) and the pyridine carboxylic acid (0.055 g, 0.148 mmol, 1.0 eq) indimethylformamide (1.5 mL) was added triethylamine (0.031 mL, 0.222mmol, 1.5 eq) followed by HATU (0.056 g, 0.148 mmol, 1.0 eq). Theresulting yellow solution was stirred at room temperature for 5 hoursbefore partitioning between EtOAc (100 mL) and NaHCO₃-water (1:1, 100mL). The organics were further washed with brine (100 mL), water (100mL) and brine (100 mL) before drying (Na₂SO₄) and concentrating underreduced pressure. MPLC (0→10% MeOH—CH₂Cl₂) yielded the diamide (0.057 g,67%) as a white foam; ¹H nmr (CDCl₃) δ 8.97 (1H, s, pyH-6), 8.17 (1H,dd, J 8.0, 2.0 Hz, pyH-4), 7.93 (2H, d, J 9.5 Hz, 2H of C₆H₄OCH₃), 7.60(1H, d, J 8.5 Hz, pyH-4), 7.07 (1H, m, NH), 6.94 (2H, d, J 9.0 Hz, 2H ofC₆H₄OCH₃), 4.66 (1H, m, 1H of BzpipH-2, H-6), 4.55 (1H, m, 1H ofpipH-2), 4.42 (1H, m, 1H of pipH-2), 4.19 (1H, m, pipH-4), 3.90 (1H, m,1H of BzpipH-2, H-6), 3.87 (3H, s, OCH₃), 3.52 (1H, m, BzpipH-4), 3.24(1H, m, 1H of BzpipH-2, H-6), 3.09 (1H, m, 1H of BzpipH-2, H-6),3.05-2.87 (2H, m, pipH-6), 2.04-1.99 (2H, m, 2H of pipH-5, BzpipH-3,H-5), 1.91-1.67 (4H, m, 4H of pipH-5, BzpipH-3, H-5), 1.46 (9H, s,C(CH₃)₃); m/z: 587 [M+H]⁺.

Syntheses of (cis)- and (trans)-tert-butyl4-amino-3-fluoropiperidine-1-carboxylate

For use in the synthesis of various compounds described above, (cis)-and (trans)-tert-butyl 4-amino-3-fluoropiperidine-1-carboxylate wereprepared as described in the scheme below:

Example 2 Increase in AMPK Activity

Compounds were assayed for their ability to activate AMPK using anenzyme-linked immunosorbent assay. Reagents and procedures for measuringAMPK activation are well known and kits for AMPK activation assays arecommercially available. The EC₅₀ values for AMPK activation forcompounds 1-498 are presented in Table 2 below, in which “A” is lessthan 0.5 μM; “B” is 0.5-1 μM; “C” is 1-5 μM; and “D” is 5-10 μM; and “E”is >10 μM:

TABLE 2 Cpd No. AMPK EC₅₀ 1 A 2 E 3 B 4 B 5 B 6 B 7 A 8 A 9 A 10 A 11 A12 D 13 C 14 B 15 C 16 A 17 E 18 A 19 F 20 F 21 A 22 A 23 A 24 A 25 A 26A 27 B 28 B 29 B 30 C 31 A 32 B 33 D 34 C 35 B 36 B 37 D 38 B 39 C 40 C41 E 42 C 43 C 47 A 48 B 49 A 50 A 51 A 52 A 53 A 54 A 55 A 56 A 57 A 58A 59 A 60 A 61 A 62 A 63 A 64 A 65 A 66 A 67 A 68 A 69 A 70 A 72 A 73 D74 A 75 C 76 A 77 A 78 A 79 B 80 C 81 B 82 B 83 E 84 C 85 C 86 C 87 C 88C 89 C 90 E 91 E 92 E 93 E 94 E 95 A 96 E 97 C 98 C 99 D 100 A 101 A 102D 103 A 104 A 105 E 106 D 107 D 108 B 109 D 110 C 111 C 112 C 113 C 114C 115 D 116 C 117 A 118 A 119 C 120 E 121 C 122 A 123 A 124 A 125 A 126A 127 A 128 A 129 A 130 A 131 A 132 A 133 A 134 A 135 A 136 A 137 A 138A 139 A 140 A 141 B 142 A 143 A 144 B 145 A 146 A 147 A 149 B 150 A 151A 152 A 153 C 154 A 155 A 156 A 157 A 158 A 159 C 160 A 161 A 162 A 163A 164 B 165 A 166 A 167 A 168 A 169 B 170 E 171 A 172 A 173 A 174 A 175A 176 C 177 C 178 A 179 A 180 A 181 A 182 A 183 A 184 A 185 A 186 A 187C 188 B 189 C 190 A 191 A 192 A 193 A 194 A 195 A 196 A 197 A 198 A 199A 200 A 201 B 202 A 203 A 204 A 205 A 206 A 207 A 208 A 209 A 210 E 211A 212 A 213 A 214 E 215 E 216 E 217 E 218 A 219 A 220 A 221 C 222 C 223C 224 A 225 A 226 A 227 A 228 A 229 C 230 B 231 A 232 A 233 A 234 A 235A 236 A 237 C 238 C 239 C 240 A 241 A 242 A 243 A 244 D 245 A 246 A 247A 248 A 249 A 250 A 251 A 252 B 253 B 254 A 255 A 256 A 257 A 258 A 259A 260 A 261 A 262 A 263 A 264 D 265 C 266 A 267 A 268 A 269 A 270 A 271A 272 A 273 A 274 E 275 A 276 A 277 A 278 A 279 A 280 A 281 A 282 A 283A 284 A 285 A 286 A 287 A 288 A 289 A 290 A 291 A 292 A 293 A 294 A 295A 296 A 297 A 298 A 299 A 300 A 301 A 302 A 303 A 304 A 305 A 306 A 307B 308 A 309 A 310 A 311 A 312 A 313 A 314 E 315 A 316 A 317 A 318 A 319A 320 A 321 A 322 A 323 A 324 A 325 A 326 A 327 A 328 A 329 A 330 B 331A 332 A 333 A 334 A 335 E 336 A 337 A 338 A 339 A 340 A 341 A 342 A 343A 344 A 345 A 346 A 347 A 348 A 349 A 350 A 351 A 352 A 353 A 354 A 355E 356 A 357 A 358 A 359 A 360 A 361 A 362 A 363 A 364 A 365 A 366 A 367E 368 A 369 A 370 A 371 E 372 A 373 A 374 E 375 A 376 A 377 A 378 A 379A 380 A 381 A 382 A 383 E 384 B 385 E 386 E 387 A 388 A 389 C 390 A 391A 392 A 393 A 394 E 395 A 396 C 397 A 398 A 399 A 400 C 401 C 402 A 403E 404 C 405 A 406 B 407 A 408 A 409 A 410 A 411 C 412 C 413 C 414 C 415A 416 C 417 A 418 A 419 A 420 C 421 C 422 C 423 A 424 A 425 A 426 A 427C 428 B 429 B 430 A 431 B 432 B 433 A 434 A 435 A 436 A 437 A 438 A 439A 440 A 441 A 442 A 443 A 444 A 445 E 446 A 447 A 448 C 449 C 450 A 451A 452 A 453 A 454 A 455 A 456 A 457 A 458 A 459 A 460 A 461 A 462 A 463A 464 A 465 A 466 A 467 C 468 A 469 A 470 A 471 C 472 C 473 C 474 C 475C 476 A 477 A 478 A 479 A 480 A 481 A 482 A 483 A 484 A 485 A 486 A 487C 488 A 489 A 490 C 491 C 492 A 493 A 494 A 495 A 496 A 497 A 498 A

What is claimed is: 1.N-((trans)-1-(4-cyanobenzyl)-3-fluoropiperidin-4-yl)-6-(4-(4-methoxybenzoyl)piperidine-1-carbonyl)nicotinamideor a pharmaceutically acceptable salt or N-oxide thereof.
 2. Apharmaceutical composition comprising: at least one pharmaceuticallyacceptable carrier, diluent or excipient; and a compound according toclaim 1 or a pharmaceutically acceptable salt or N-oxide thereof.
 3. Amethod for activating the AMPK pathway in a cell, the method comprisingcontacting the cell with an effective amount of a compound according toclaim 1 or a pharmaceutically acceptable salt or N-oxide thereof.
 4. Amethod for treating type II diabetes in a subject, the method comprisingadministering to the subject an effective amount of a compound accordingto claim 1 or a pharmaceutically acceptable salt or N-oxide thereof. 5.A method for treating atherosclerosis in a subject, the methodcomprising administering to the subject an effective amount of acompound according to claim 1 or a pharmaceutically acceptable salt orN-oxide thereof.
 6. A method for improving exercise efficiency in asubject, the method comprising administering to the subject an effectiveamount of a compound according to claim 1 or a pharmaceuticallyacceptable salt or N-oxide thereof.
 7. A method for treatingintermittent claudication, the method comprising administering to thesubject an effective amount of a compound according to claim 1 or apharmaceutically acceptable salt or N-oxide thereof.
 8. The compound ofclaim 1, having the structural formula


9. A pharmaceutical composition comprising: at least onepharmaceutically acceptable carrier, diluent or excipient; and acompound according to claim 8 or a pharmaceutically acceptable salt orN-oxide thereof.
 10. A method for activating the AMPK pathway in a cell,the method comprising contacting the cell with an effective amount of acompound according to claim 8 or a pharmaceutically acceptable salt orN-oxide thereof.
 11. A method for treating type II diabetes in asubject, the method comprising administering to the subject an effectiveamount of a compound according to claim 8 or a pharmaceuticallyacceptable salt or N-oxide thereof.
 12. A method for treatingatherosclerosis in a subject, the method comprising administering to thesubject an effective amount of a compound according to claim 8 or apharmaceutically acceptable salt or N-oxide thereof.
 13. A method forimproving exercise efficiency in a subject, the method comprisingadministering to the subject an effective amount of a compound accordingto claim 8 or a pharmaceutically acceptable salt or N-oxide thereof. 14.A method for treating intermittent claudication, the method comprisingadministering to the subject an effective amount of a compound accordingto claim 8 or a pharmaceutically acceptable salt or N-oxide thereof. 15.The compound of claim 1, having the structural formula


16. A pharmaceutical composition comprising: at least onepharmaceutically acceptable carrier, diluent or excipient; and acompound according to claim 15 or a pharmaceutically acceptable salt orN-oxide thereof.
 17. A method for activating the AMPK pathway in a cell,the method comprising contacting the cell with an effective amount of acompound according to claim 15 or a pharmaceutically acceptable salt orN-oxide thereof.
 18. A method for treating type II diabetes in asubject, the method comprising administering to the subject an effectiveamount of a compound according to claim 15 or a pharmaceuticallyacceptable salt or N-oxide thereof.
 19. A method for treatingatherosclerosis in a subject, the method comprising administering to thesubject an effective amount of a compound according to claim 15 or apharmaceutically acceptable salt or N-oxide thereof.
 20. A method forimproving exercise efficiency in a subject, the method comprisingadministering to the subject an effective amount of a compound accordingto claim 15 or a pharmaceutically acceptable salt or N-oxide thereof.21. A method for treating intermittent claudication, the methodcomprising administering to the subject an effective amount of acompound according to claim 15 or a pharmaceutically acceptable salt orN-oxide thereof.
 22. A compound according to claim 1, wherein thecompound is racemic.
 23. A compound according to claim 8, wherein thecompound is substantially enantiomerically pure.
 24. A compoundaccording to claim 15, wherein the compound is substantiallyenantiomerically pure.